Daily Papers

In recent years, diffusion models trained on equilibrium molecular distributions have proven effective for sampling biomolecules. Beyond direct sampling, the score of such a model can also be used to derive the forces that act on molecular systems. However, while classical diffusion sampling usually recovers the training distribution, the corresponding energy-based interpretation of the learned score is often inconsistent with this distribution, even for low-dimensional toy systems. We trace this inconsistency to inaccuracies of the learned score at very small diffusion timesteps, where the model must capture the correct evolution of the data distribution. In this regime, diffusion models fail to satisfy the Fokker--Planck equation, which governs the evolution of the score. We interpret this deviation as one source of the observed inconsistencies and propose an energy-based diffusion model with a Fokker--Planck-derived regularization term to enforce consistency. We demonstrate our approach by sampling and simulating multiple biomolecular systems, including fast-folding proteins, and by introducing a state-of-the-art transferable Boltzmann emulator for dipeptides that supports simulation and achieves improved consistency and efficient sampling. Our code, model weights, and self-contained JAX and PyTorch notebooks are available at https://github.com/noegroup/ScoreMD.

Spherical equivariant graph neural networks (EGNNs) provide a principled framework for learning on three-dimensional molecular and biomolecular systems, where predictions must respect the rotational symmetries inherent in physics. These models extend traditional message-passing GNNs and Transformers by representing node and edge features as spherical tensors that transform under irreducible representations of the rotation group SO(3), ensuring that predictions change in physically meaningful ways under rotations of the input. This guide develops a complete, intuitive foundation for spherical equivariant modeling - from group representations and spherical harmonics, to tensor products, Clebsch-Gordan decomposition, and the construction of SO(3)-equivariant kernels. Building on this foundation, we construct the Tensor Field Network and SE(3)-Transformer architectures and explain how they perform equivariant message-passing and attention on geometric graphs. Through clear mathematical derivations and annotated code excerpts, this guide serves as a self-contained introduction for researchers and learners seeking to understand or implement spherical EGNNs for applications in chemistry, molecular property prediction, protein structure modeling, and generative modeling.

Simulating trajectories of multi-particle systems on complex energy landscapes is a central task in molecular dynamics (MD) and drug discovery, but remains challenging at scale due to computationally expensive and long simulations. Previous approaches leverage techniques such as flow or Schrödinger bridge matching to implicitly learn joint trajectories through data snapshots. However, many systems, including biomolecular systems and heterogeneous cell populations, undergo dynamic interactions that evolve over their trajectory and cannot be captured through static snapshots. To close this gap, we introduce Entangled Schrödinger Bridge Matching (EntangledSBM), a framework that learns the first- and second-order stochastic dynamics of interacting, multi-particle systems where the direction and magnitude of each particle's path depend dynamically on the paths of the other particles. We define the Entangled Schrödinger Bridge (EntangledSB) problem as solving a coupled system of bias forces that entangle particle velocities. We show that our framework accurately simulates heterogeneous cell populations under perturbations and rare transitions in high-dimensional biomolecular systems.

Complex networks have become essential tools for understanding diverse phenomena in social systems, traffic systems, biomolecular systems, and financial systems. Identifying critical nodes is a central theme in contemporary research, serving as a vital bridge between theoretical foundations and practical applications. Nevertheless, the intrinsic complexity and structural heterogeneity characterizing real-world networks, with particular emphasis on dynamic and higher-order networks, present substantial obstacles to the development of universal frameworks for critical node identification. This paper provides a comprehensive review of critical node identification techniques, categorizing them into seven main classes: centrality, critical nodes deletion problem, influence maximization, network control, artificial intelligence, higher-order and dynamic methods. Our review bridges the gaps in existing surveys by systematically classifying methods based on their methodological foundations and practical implications, and by highlighting their strengths, limitations, and applicability across different network types. Our work enhances the understanding of critical node research by identifying key challenges, such as algorithmic universality, real-time evaluation in dynamic networks, analysis of higher-order structures, and computational efficiency in large-scale networks. The structured synthesis consolidates current progress and highlights open questions, particularly in modeling temporal dynamics, advancing efficient algorithms, integrating machine learning approaches, and developing scalable and interpretable metrics for complex systems.

The development of reliable and extensible molecular mechanics (MM) force fields -- fast, empirical models characterizing the potential energy surface of molecular systems -- is indispensable for biomolecular simulation and computer-aided drug design. Here, we introduce a generalized and extensible machine-learned MM force field, espaloma-0.3, and an end-to-end differentiable framework using graph neural networks to overcome the limitations of traditional rule-based methods. Trained in a single GPU-day to fit a large and diverse quantum chemical dataset of over 1.1M energy and force calculations, espaloma-0.3 reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids. Moreover, this force field maintains the quantum chemical energy-minimized geometries of small molecules and preserves the condensed phase properties of peptides, self-consistently parametrizing proteins and ligands to produce stable simulations leading to highly accurate predictions of binding free energies. This methodology demonstrates significant promise as a path forward for systematically building more accurate force fields that are easily extensible to new chemical domains of interest.

Self-supervised training of language models (LMs) has seen great success for protein sequences in learning meaningful representations and for generative drug design. Most protein LMs are based on the Transformer architecture trained on individual proteins with short context lengths. Such protein LMs cannot extrapolate to longer proteins and protein complexes well. They also fail to account for the underlying biological mechanisms carried out by biomolecular interactions and dynamics i.e., proteins often interact with other proteins, molecules, and pathways in complex biological systems. In this work, we propose LC-PLM based on an alternative protein LM architecture, BiMamba-S, built off selective structured state-space models, to learn high-quality universal protein representations at the amino acid token level using masked language modeling. We also introduce its graph-contextual variant, LC-PLM-G, which contextualizes protein-protein interaction (PPI) graphs for a second stage of training. LC-PLM demonstrates favorable neural scaling laws, better length extrapolation capability, and a 7% to 34% improvement on protein downstream tasks than Transformer-based ESM-2. LC-PLM-G further trained within the context of PPI graphs shows promising results on protein structure and function prediction tasks. Our study demonstrates the benefit of increasing the context size with computationally efficient LM architecture (e.g. structured state space models) in learning universal protein representations and incorporating molecular interaction context contained in biological graphs.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Understanding and designing biomolecules, such as proteins and small molecules, is central to advancing drug discovery, synthetic biology, and enzyme engineering. Recent breakthroughs in Artificial Intelligence (AI) have revolutionized biomolecular research, achieving remarkable accuracy in biomolecular prediction and design. However, a critical gap remains between AI's computational power and researchers' intuition, using natural language to align molecular complexity with human intentions. Large Language Models (LLMs) have shown potential to interpret human intentions, yet their application to biomolecular research remains nascent due to challenges including specialized knowledge requirements, multimodal data integration, and semantic alignment between natural language and biomolecules. To address these limitations, we present InstructBioMol, a novel LLM designed to bridge natural language and biomolecules through a comprehensive any-to-any alignment of natural language, molecules, and proteins. This model can integrate multimodal biomolecules as input, and enable researchers to articulate design goals in natural language, providing biomolecular outputs that meet precise biological needs. Experimental results demonstrate InstructBioMol can understand and design biomolecules following human instructions. Notably, it can generate drug molecules with a 10% improvement in binding affinity and design enzymes that achieve an ESP Score of 70.4, making it the only method to surpass the enzyme-substrate interaction threshold of 60.0 recommended by the ESP developer. This highlights its potential to transform real-world biomolecular research.

Biomolecular interactions underpin almost all biological processes, and their rational design is central to programming new biological functions. Generative AI models have emerged as powerful tools for molecular design, yet most remain specialized for individual molecular types and lack fine-grained control over interaction details. Here we present ODesign, an all-atom generative world model for all-to-all biomolecular interaction design. ODesign allows scientists to specify epitopes on arbitrary targets and generate diverse classes of binding partners with fine-grained control. Across entity-, token-, and atom-level benchmarks in the protein modality, ODesign demonstrates superior controllability and performance to modality-specific baselines. Extending beyond proteins, it generalizes to nucleic acid and small-molecule design, enabling interaction types such as protein-binding RNA/DNA and RNA/DNA-binding ligands that were previously inaccessible. By unifying multimodal biomolecular interactions within a single generative framework, ODesign moves toward a general-purpose molecular world model capable of programmable design. ODesign is available at https://odesign.lglab.ac.cn ,

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Many examples of cooperation exist in biology. In chemical systems however, which can sometimes be quite complex, we do not appear to observe intricate cooperative interactions. A key question for the origin of life, is then how can molecular cooperation first arise in an abiotic system prior to the emergence of biological replication. We postulate that selection at the molecular level is a driving force behind the complexification of chemical systems, particularly during the origins of life. In the theory of multilevel selection the two selective forces are: within-group and between-group, where the former tends to favor "selfish" replication of individuals and the latter favor cooperation between individuals enhancing the replication of the group as a whole. These forces can be quantified using the Price equation, which is a standard tool used in evolutionary biology to quantify evolutionary change. Our central claim is that replication and heredity in chemical systems are subject to selection, and quantifiable using the multilevel Price equation. We demonstrate this using the Graded Autocatalysis Replication Domain computer model, describing simple protocell composed out of molecules and its replication, which respectively analogue to the group and the individuals. In contrast to previous treatments of this model, we treat the lipid molecules themselves as replicating individuals and the protocells they form as groups of individuals. Our goal is to demonstrate how evolutionary biology tools and concepts can be applied in chemistry and we suggest that molecular cooperation may arise as a result of group selection. Further, the biological relation of parent-progeny is proposed to be analogue to the reactant-product relation in chemistry, thus allowing for tools from evolutionary biology to be applied to chemistry and would deepen the connection between chemistry and biology.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose BioT5, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. BioT5 utilizes SELFIES for 100% robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, BioT5 distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at https://github.com/QizhiPei/BioT5{Github}.

Polymers-macromolecular systems composed of repeating chemical units-constitute the molecular foundation of living organisms, while their synthetic counterparts drive transformative advances across medicine, consumer products, and energy technologies. While machine learning (ML) models have been trained on millions of quantum chemical atomistic simulations for materials and/or small molecular structures to enable efficient, accurate, and transferable predictions of chemical properties, polymers have largely not been included in prior datasets due to the computational expense of high quality electronic structure calculations on representative polymeric structures. Here, we address this shortcoming with the creation of the Open Polymers 2026 (OPoly26) dataset, which contains more than 6.57 million density functional theory (DFT) calculations on up to 360 atom clusters derived from polymeric systems, comprising over 1.2 billion total atoms. OPoly26 captures the chemical diversity that makes polymers intrinsically tunable and versatile materials, encompassing variations in monomer composition, degree of polymerization, chain architectures, and solvation environments. We show that augmenting ML model training with the OPoly26 dataset improves model performance for polymer prediction tasks. We also publicly release the OPoly26 dataset to help further the development of ML models for polymers, and more broadly, strive towards universal atomistic models.

Foundation models (FMs) have exhibited remarkable performance across a wide range of downstream tasks in many domains. Nevertheless, general-purpose FMs often face challenges when confronted with domain-specific problems, due to their limited access to the proprietary training data in a particular domain. In biomedicine, there are various biological modalities, such as molecules, proteins, and cells, which are encoded by the language of life and exhibit significant modality gaps with human natural language. In this paper, we introduce BioMedGPT, an open multimodal generative pre-trained transformer (GPT) for biomedicine, to bridge the gap between the language of life and human natural language. BioMedGPT allows users to easily ``communicate'' with diverse biological modalities through free text, which is the first of its kind. BioMedGPT aligns different biological modalities with natural language via a large generative language model, namely, BioMedGPT-LM. We publish BioMedGPT-10B, which unifies the feature spaces of molecules, proteins, and natural language via encoding and alignment. Through fine-tuning, BioMedGPT-10B outperforms or is on par with human and significantly larger general-purpose foundation models on the biomedical QA task. It also demonstrates promising performance in the molecule QA and protein QA tasks, which could greatly accelerate the discovery of new drugs and therapeutic targets. In addition, BioMedGPT-LM-7B is the first large generative language model based on Llama2 in the biomedical domain, therefore is commercial friendly. Both BioMedGPT-10B and BioMedGPT-LM-7B are open-sourced to the research community. In addition, we publish the datasets that are meticulously curated for the alignment of multi-modalities, i.e., PubChemQA and UniProtQA. All the models, codes, and datasets are available at https://github.com/PharMolix/OpenBioMed.

Foundation models applied to bio-molecular space hold promise to accelerate drug discovery. Molecular representation is key to building such models. Previous works have typically focused on a single representation or view of the molecules. Here, we develop a multi-view foundation model approach, that integrates molecular views of graph, image and text. Single-view foundation models are each pre-trained on a dataset of up to 200M molecules and then aggregated into combined representations. Our multi-view model is validated on a diverse set of 18 tasks, encompassing ligand-protein binding, molecular solubility, metabolism and toxicity. We show that the multi-view models perform robustly and are able to balance the strengths and weaknesses of specific views. We then apply this model to screen compounds against a large (>100 targets) set of G Protein-Coupled receptors (GPCRs). From this library of targets, we identify 33 that are related to Alzheimer's disease. On this subset, we employ our model to identify strong binders, which are validated through structure-based modeling and identification of key binding motifs.

Modern life sciences research is increasingly relying on artificial intelligence approaches to model biological systems, primarily centered around the use of machine learning (ML) models. Although ML is undeniably useful for identifying patterns in large, complex data sets, its widespread application in biological sciences represents a significant deviation from traditional methods of scientific inquiry. As such, the interplay between these models and scientific understanding in biology is a topic with important implications for the future of scientific research, yet it is a subject that has received little attention. Here, we draw from an epistemological toolkit to contextualize recent applications of ML in biological sciences under modern philosophical theories of understanding, identifying general principles that can guide the design and application of ML systems to model biological phenomena and advance scientific knowledge. We propose that conceptions of scientific understanding as information compression, qualitative intelligibility, and dependency relation modelling provide a useful framework for interpreting ML-mediated understanding of biological systems. Through a detailed analysis of two key application areas of ML in modern biological research - protein structure prediction and single cell RNA-sequencing - we explore how these features have thus far enabled ML systems to advance scientific understanding of their target phenomena, how they may guide the development of future ML models, and the key obstacles that remain in preventing ML from achieving its potential as a tool for biological discovery. Consideration of the epistemological features of ML applications in biology will improve the prospects of these methods to solve important problems and advance scientific understanding of living systems.

Proteins, as essential biomolecules, play a central role in biological processes, including metabolic reactions and DNA replication. Accurate prediction of their properties and functions is crucial in biological applications. Recent development of protein language models (pLMs) with supervised fine tuning provides a promising solution to this problem. However, the fine-tuned model is tailored for particular downstream prediction task, and achieving general-purpose protein understanding remains a challenge. In this paper, we introduce Structure-Enhanced Protein Instruction Tuning (SEPIT) framework to bridge this gap. Our approach integrates a noval structure-aware module into pLMs to inform them with structural knowledge, and then connects these enhanced pLMs to large language models (LLMs) to generate understanding of proteins. In this framework, we propose a novel two-stage instruction tuning pipeline that first establishes a basic understanding of proteins through caption-based instructions and then refines this understanding using a mixture of experts (MoEs) to learn more complex properties and functional information with the same amount of activated parameters. Moreover, we construct the largest and most comprehensive protein instruction dataset to date, which allows us to train and evaluate the general-purpose protein understanding model. Extensive experimental results on open-ended generation and closed-set answer tasks demonstrate the superior performance of SEPIT over both closed-source general LLMs and open-source LLMs trained with protein knowledge.

Computational methods that operate on three-dimensional molecular structure have the potential to solve important questions in biology and chemistry. In particular, deep neural networks have gained significant attention, but their widespread adoption in the biomolecular domain has been limited by a lack of either systematic performance benchmarks or a unified toolkit for interacting with molecular data. To address this, we present ATOM3D, a collection of both novel and existing benchmark datasets spanning several key classes of biomolecules. We implement several classes of three-dimensional molecular learning methods for each of these tasks and show that they consistently improve performance relative to methods based on one- and two-dimensional representations. The specific choice of architecture proves to be critical for performance, with three-dimensional convolutional networks excelling at tasks involving complex geometries, graph networks performing well on systems requiring detailed positional information, and the more recently developed equivariant networks showing significant promise. Our results indicate that many molecular problems stand to gain from three-dimensional molecular learning, and that there is potential for improvement on many tasks which remain underexplored. To lower the barrier to entry and facilitate further developments in the field, we also provide a comprehensive suite of tools for dataset processing, model training, and evaluation in our open-source atom3d Python package. All datasets are available for download from https://www.atom3d.ai .

The interactions between DNA, RNA, and proteins are fundamental to biological processes, as illustrated by the central dogma of molecular biology. Although modern biological pre-trained models have achieved great success in analyzing these macromolecules individually, their interconnected nature remains underexplored. This paper follows the guidance of the central dogma to redesign both the data and model pipeline and offers a comprehensive framework, Life-Code, that spans different biological functions. As for data flow, we propose a unified pipeline to integrate multi-omics data by reverse-transcribing RNA and reverse-translating amino acids into nucleotide-based sequences. As for the model, we design a codon tokenizer and a hybrid long-sequence architecture to encode the interactions between coding and non-coding regions through masked modeling pre-training. To model the translation and folding process with coding sequences, Life-Code learns protein structures of the corresponding amino acids by knowledge distillation from off-the-shelf protein language models. Such designs enable Life-Code to capture complex interactions within genetic sequences, providing a more comprehensive understanding of multi-omics with the central dogma. Extensive experiments show that Life-Code achieves state-of-the-art results on various tasks across three omics, highlighting its potential for advancing multi-omics analysis and interpretation.

Proteins power a vast array of functional processes in living cells. The capability to create new proteins with designed structures and functions would thus enable the engineering of cellular behavior and development of protein-based therapeutics and materials. Structure-based protein design aims to find structures that are designable (can be realized by a protein sequence), novel (have dissimilar geometry from natural proteins), and diverse (span a wide range of geometries). While advances in protein structure prediction have made it possible to predict structures of novel protein sequences, the combinatorially large space of sequences and structures limits the practicality of search-based methods. Generative models provide a compelling alternative, by implicitly learning the low-dimensional structure of complex data distributions. Here, we leverage recent advances in denoising diffusion probabilistic models and equivariant neural networks to develop Genie, a generative model of protein structures that performs discrete-time diffusion using a cloud of oriented reference frames in 3D space. Through in silico evaluations, we demonstrate that Genie generates protein backbones that are more designable, novel, and diverse than existing models. This indicates that Genie is capturing key aspects of the distribution of protein structure space and facilitates protein design with high success rates. Code for generating new proteins and training new versions of Genie is available at https://github.com/aqlaboratory/genie.

Machine learning, notably deep learning, has significantly propelled molecular investigations within the biochemical sphere. Traditionally, modeling for such research has centered around a handful of paradigms. For instance, the prediction paradigm is frequently deployed for tasks such as molecular property prediction. To enhance the generation and decipherability of purely data-driven models, scholars have integrated biochemical domain knowledge into these molecular study models. This integration has sparked a surge in paradigm transfer, which is solving one molecular learning task by reformulating it as another one. With the emergence of Large Language Models, these paradigms have demonstrated an escalating trend towards harmonized unification. In this work, we delineate a literature survey focused on knowledge-informed molecular learning from the perspective of paradigm transfer. We classify the paradigms, scrutinize their methodologies, and dissect the contribution of domain knowledge. Moreover, we encapsulate prevailing trends and identify intriguing avenues for future exploration in molecular learning.

Proteins are dynamic molecular machines whose biological functions, spanning enzymatic catalysis, signal transduction, and structural adaptation, are intrinsically linked to their motions. Designing proteins with targeted dynamic properties, however, remains a challenge due to the complex, degenerate relationships between sequence, structure, and molecular motion. Here, we introduce VibeGen, a generative AI framework that enables end-to-end de novo protein design conditioned on normal mode vibrations. VibeGen employs an agentic dual-model architecture, comprising a protein designer that generates sequence candidates based on specified vibrational modes and a protein predictor that evaluates their dynamic accuracy. This approach synergizes diversity, accuracy, and novelty during the design process. Via full-atom molecular simulations as direct validation, we demonstrate that the designed proteins accurately reproduce the prescribed normal mode amplitudes across the backbone while adopting various stable, functionally relevant structures. Notably, generated sequences are de novo, exhibiting no significant similarity to natural proteins, thereby expanding the accessible protein space beyond evolutionary constraints. Our work integrates protein dynamics into generative protein design, and establishes a direct, bidirectional link between sequence and vibrational behavior, unlocking new pathways for engineering biomolecules with tailored dynamical and functional properties. This framework holds broad implications for the rational design of flexible enzymes, dynamic scaffolds, and biomaterials, paving the way toward dynamics-informed AI-driven protein engineering.

The discovery and identification of molecules in biological and environmental samples is crucial for advancing biomedical and chemical sciences. Tandem mass spectrometry (MS/MS) is the leading technique for high-throughput elucidation of molecular structures. However, decoding a molecular structure from its mass spectrum is exceptionally challenging, even when performed by human experts. As a result, the vast majority of acquired MS/MS spectra remain uninterpreted, thereby limiting our understanding of the underlying (bio)chemical processes. Despite decades of progress in machine learning applications for predicting molecular structures from MS/MS spectra, the development of new methods is severely hindered by the lack of standard datasets and evaluation protocols. To address this problem, we propose MassSpecGym -- the first comprehensive benchmark for the discovery and identification of molecules from MS/MS data. Our benchmark comprises the largest publicly available collection of high-quality labeled MS/MS spectra and defines three MS/MS annotation challenges: de novo molecular structure generation, molecule retrieval, and spectrum simulation. It includes new evaluation metrics and a generalization-demanding data split, therefore standardizing the MS/MS annotation tasks and rendering the problem accessible to the broad machine learning community. MassSpecGym is publicly available at https://github.com/pluskal-lab/MassSpecGym.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Structural biology relies on accurate three-dimensional biomolecular structures to advance our understanding of biological functions, disease mechanisms, and therapeutics. While recent advances in deep learning have enabled the development of all-atom foundation models for molecular modeling and generation, existing approaches face challenges in generalization due to the multi-modal nature of atomic data and the lack of comprehensive analysis of training and sampling strategies. To address these limitations, we propose PharMolixFM, a unified framework for constructing all-atom foundation models based on multi-modal generative techniques. Our framework includes three variants using state-of-the-art multi-modal generative models. By formulating molecular tasks as a generalized denoising process with task-specific priors, PharMolixFM achieves robust performance across various structural biology applications. Experimental results demonstrate that PharMolixFM-Diff achieves competitive prediction accuracy in protein-small-molecule docking (83.9% vs. 90.2% RMSD < 2Å, given pocket) with significantly improved inference speed. Moreover, we explore the empirical inference scaling law by introducing more sampling repeats or steps. Our code and model are available at https://github.com/PharMolix/OpenBioMed.

RNA is a vital biomolecule with numerous roles and functions within cells, and interest in targeting it for therapeutic purposes has grown significantly in recent years. However, fully understanding and predicting RNA behavior, particularly for applications in drug discovery, remains a challenge due to the complexity of RNA structures and interactions. While foundational models in biology have demonstrated success in modeling several biomolecules, especially proteins, achieving similar breakthroughs for RNA has proven more difficult. Current RNA models have yet to match the performance observed in the protein domain, leaving an important gap in computational biology. In this work, we present ChaRNABERT, a suite of sample and parameter-efficient RNA foundational models, that through a learnable tokenization process, are able to reach state-of-the-art performance on several tasks in established benchmarks. We extend its testing in relevant downstream tasks such as RNA-protein and aptamer-protein interaction prediction. Weights and inference code for ChaRNABERT-8M will be provided for academic research use. The other models will be available upon request.

Predicting gene function from its DNA sequence is a fundamental challenge in biology. Many deep learning models have been proposed to embed DNA sequences and predict their enzymatic function, leveraging information in public databases linking DNA sequences to an enzymatic function label. However, much of the scientific community's knowledge of biological function is not represented in these categorical labels, and is instead captured in unstructured text descriptions of mechanisms, reactions, and enzyme behavior. These descriptions are often captured alongside DNA sequences in biological databases, albeit in an unstructured manner. Deep learning of models predicting enzymatic function are likely to benefit from incorporating this multi-modal data encoding scientific knowledge of biological function. There is, however, no dataset designed for machine learning algorithms to leverage this multi-modal information. Here we propose a novel dataset and benchmark suite that enables the exploration and development of large multi-modal neural network models on gene DNA sequences and natural language descriptions of gene function. We present baseline performance on benchmarks for both unsupervised and supervised tasks that demonstrate the difficulty of this modeling objective, while demonstrating the potential benefit of incorporating multi-modal data types in function prediction compared to DNA sequences alone. Our dataset is at: https://hoarfrost-lab.github.io/BioTalk/.

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences.This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs.We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the English similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 76%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data.This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study opens a new door for AI-driven biological research.

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

Recently, pre-trained foundation models have enabled significant advancements in multiple fields. In molecular machine learning, however, where datasets are often hand-curated, and hence typically small, the lack of datasets with labeled features, and codebases to manage those datasets, has hindered the development of foundation models. In this work, we present seven novel datasets categorized by size into three distinct categories: ToyMix, LargeMix and UltraLarge. These datasets push the boundaries in both the scale and the diversity of supervised labels for molecular learning. They cover nearly 100 million molecules and over 3000 sparsely defined tasks, totaling more than 13 billion individual labels of both quantum and biological nature. In comparison, our datasets contain 300 times more data points than the widely used OGB-LSC PCQM4Mv2 dataset, and 13 times more than the quantum-only QM1B dataset. In addition, to support the development of foundational models based on our proposed datasets, we present the Graphium graph machine learning library which simplifies the process of building and training molecular machine learning models for multi-task and multi-level molecular datasets. Finally, we present a range of baseline results as a starting point of multi-task and multi-level training on these datasets. Empirically, we observe that performance on low-resource biological datasets show improvement by also training on large amounts of quantum data. This indicates that there may be potential in multi-task and multi-level training of a foundation model and fine-tuning it to resource-constrained downstream tasks.

Large Language Models (LLMs), with their remarkable task-handling capabilities and innovative outputs, have catalyzed significant advancements across a spectrum of fields. However, their proficiency within specialized domains such as biomolecular studies remains limited. To address this challenge, we introduce Mol-Instructions, a meticulously curated, comprehensive instruction dataset expressly designed for the biomolecular realm. Mol-Instructions is composed of three pivotal components: molecule-oriented instructions, protein-oriented instructions, and biomolecular text instructions, each curated to enhance the understanding and prediction capabilities of LLMs concerning biomolecular features and behaviors. Through extensive instruction tuning experiments on the representative LLM, we underscore the potency of Mol-Instructions to enhance the adaptability and cognitive acuity of large models within the complex sphere of biomolecular studies, thereby promoting advancements in the biomolecular research community. Mol-Instructions is made publicly accessible for future research endeavors and will be subjected to continual updates for enhanced applicability.

Complex hierarchical structures composed of simple nanoscale building blocks form the basis of most biological materials. Here we demonstrate how analogies between seemingly different fields enable the understanding of general principles by which functional properties in hierarchical systems emerge, similar to an analogy learning process. Specifically, natural hierarchical materials like spider silk exhibit properties comparable to classical music in terms of their hierarchical structure and function. As a comparative tool here we apply hierarchical ontology logs (olog) that follow a rigorous mathematical formulation based on category theory to provide an insightful system representation by expressing knowledge in a conceptual map. We explain the process of analogy creation, draw connections at several levels of hierarchy and identify similar patterns that govern the structure of the hierarchical systems silk and music and discuss the impact of the derived analogy for nanotechnology.

The regulation of various cellular processes heavily relies on the protein complexes within a living cell, necessitating a comprehensive understanding of their three-dimensional structures to elucidate the underlying mechanisms. While neural docking techniques have exhibited promising outcomes in binary protein docking, the application of advanced neural architectures to multimeric protein docking remains uncertain. This study introduces SyNDock, an automated framework that swiftly assembles precise multimeric complexes within seconds, showcasing performance that can potentially surpass or be on par with recent advanced approaches. SyNDock possesses several appealing advantages not present in previous approaches. Firstly, SyNDock formulates multimeric protein docking as a problem of learning global transformations to holistically depict the placement of chain units of a complex, enabling a learning-centric solution. Secondly, SyNDock proposes a trainable two-step SE(3) algorithm, involving initial pairwise transformation and confidence estimation, followed by global transformation synchronization. This enables effective learning for assembling the complex in a globally consistent manner. Lastly, extensive experiments conducted on our proposed benchmark dataset demonstrate that SyNDock outperforms existing docking software in crucial performance metrics, including accuracy and runtime. For instance, it achieves a 4.5% improvement in performance and a remarkable millionfold acceleration in speed.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

The dynamics of biomolecules are crucial for our understanding of their functioning in living systems. However, current 3D imaging techniques, such as cryogenic electron microscopy (cryo-EM), require freezing the sample, which limits the observation of their conformational changes in real time. The innovative liquid-phase electron microscopy (liquid-phase EM) technique allows molecules to be placed in the native liquid environment, providing a unique opportunity to observe their dynamics. In this paper, we propose TEMPOR, a Temporal Electron MicroscoPy Object Reconstruction algorithm for liquid-phase EM that leverages an implicit neural representation (INR) and a dynamical variational auto-encoder (DVAE) to recover time series of molecular structures. We demonstrate its advantages in recovering different motion dynamics from two simulated datasets, 7bcq and Cas9. To our knowledge, our work is the first attempt to directly recover 3D structures of a temporally-varying particle from liquid-phase EM movies. It provides a promising new approach for studying molecules' 3D dynamics in structural biology.

Proteins are complex biomolecules that perform a variety of crucial functions within living organisms. Designing and generating novel proteins can pave the way for many future synthetic biology applications, including drug discovery. However, it remains a challenging computational task due to the large modeling space of protein structures. In this study, we propose a latent diffusion model that can reduce the complexity of protein modeling while flexibly capturing the distribution of natural protein structures in a condensed latent space. Specifically, we propose an equivariant protein autoencoder that embeds proteins into a latent space and then uses an equivariant diffusion model to learn the distribution of the latent protein representations. Experimental results demonstrate that our method can effectively generate novel protein backbone structures with high designability and efficiency.

A longstanding goal of biology is to identify the key genes and species that critically impact evolution, ecology, and health. Network analysis has revealed keystone species that regulate ecosystems and master regulators that regulate cellular genetic networks. Yet these studies have focused on pairwise biological interactions, which can be affected by the context of genetic background and other species present generating higher-order interactions. The important regulators of higher-order interactions are unstudied. To address this, we applied a new high-dimensional geometry approach that quantifies epistasis in a fitness landscape to ask how individual genes and species influence the interactions in the rest of the biological network. We then generated and also reanalyzed 5-dimensional datasets (two genetic, two microbiome). We identified key genes (e.g. the rbs locus and pykF) and species (e.g. Lactobacilli) that control the interactions of many other genes and species. These higher-order master regulators can induce or suppress evolutionary and ecological diversification by controlling the topography of the fitness landscape. Thus, we provide mathematical intuition and justification for exploration of biological networks in higher dimensions.

Foundation models have revolutionized natural language processing and artificial intelligence, significantly enhancing how machines comprehend and generate human languages. Inspired by the success of these foundation models, researchers have developed foundation models for individual scientific domains, including small molecules, materials, proteins, DNA, and RNA. However, these models are typically trained in isolation, lacking the ability to integrate across different scientific domains. Recognizing that entities within these domains can all be represented as sequences, which together form the "language of nature", we introduce Nature Language Model (briefly, NatureLM), a sequence-based science foundation model designed for scientific discovery. Pre-trained with data from multiple scientific domains, NatureLM offers a unified, versatile model that enables various applications including: (i) generating and optimizing small molecules, proteins, RNA, and materials using text instructions; (ii) cross-domain generation/design, such as protein-to-molecule and protein-to-RNA generation; and (iii) achieving state-of-the-art performance in tasks like SMILES-to-IUPAC translation and retrosynthesis on USPTO-50k. NatureLM offers a promising generalist approach for various scientific tasks, including drug discovery (hit generation/optimization, ADMET optimization, synthesis), novel material design, and the development of therapeutic proteins or nucleotides. We have developed NatureLM models in different sizes (1 billion, 8 billion, and 46.7 billion parameters) and observed a clear improvement in performance as the model size increases.

Antibodies are proteins produced by the immune system that can identify and neutralise a wide variety of antigens with high specificity and affinity, and constitute the most successful class of biotherapeutics. With the advent of next-generation sequencing, billions of antibody sequences have been collected in recent years, though their application in the design of better therapeutics has been constrained by the sheer volume and complexity of the data. To address this challenge, we present IgBert and IgT5, the best performing antibody-specific language models developed to date which can consistently handle both paired and unpaired variable region sequences as input. These models are trained comprehensively using the more than two billion unpaired sequences and two million paired sequences of light and heavy chains present in the Observed Antibody Space dataset. We show that our models outperform existing antibody and protein language models on a diverse range of design and regression tasks relevant to antibody engineering. This advancement marks a significant leap forward in leveraging machine learning, large scale data sets and high-performance computing for enhancing antibody design for therapeutic development.

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

Advancements in DNA sequencing technologies have significantly improved our ability to decode genomic sequences. However, the prediction and interpretation of these sequences remain challenging due to the intricate nature of genetic material. Large language models (LLMs) have introduced new opportunities for biological sequence analysis. Recent developments in genomic language models have underscored the potential of LLMs in deciphering DNA sequences. Nonetheless, existing models often face limitations in robustness and application scope, primarily due to constraints in model structure and training data scale. To address these limitations, we present GENERator, a generative genomic foundation model featuring a context length of 98k base pairs (bp) and 1.2B parameters. Trained on an expansive dataset comprising 386B bp of eukaryotic DNA, the GENERator demonstrates state-of-the-art performance across both established and newly proposed benchmarks. The model adheres to the central dogma of molecular biology, accurately generating protein-coding sequences that translate into proteins structurally analogous to known families. It also shows significant promise in sequence optimization, particularly through the prompt-responsive generation of promoter sequences with specific activity profiles. These capabilities position the GENERator as a pivotal tool for genomic research and biotechnological advancement, enhancing our ability to interpret and predict complex biological systems and enabling precise genomic interventions.

Identifying reliable synthesis pathways in materials chemistry is a complex task, particularly in polymer science, due to the intricate and often non-unique nomenclature of macromolecules. To address this challenge, we propose an agent system that integrates large language models (LLMs) and knowledge graphs (KGs). By leveraging LLMs' powerful capabilities for extracting and recognizing chemical substance names, and storing the extracted data in a structured knowledge graph, our system fully automates the retrieval of relevant literatures, extraction of reaction data, database querying, construction of retrosynthetic pathway trees, further expansion through the retrieval of additional literature and recommendation of optimal reaction pathways. A novel Multi-branched Reaction Pathway Search (MBRPS) algorithm enables the exploration of all pathways, with a particular focus on multi-branched ones, helping LLMs overcome weak reasoning in multi-branched paths. This work represents the first attempt to develop a fully automated retrosynthesis planning agent tailored specially for macromolecules powered by LLMs. Applied to polyimide synthesis, our new approach constructs a retrosynthetic pathway tree with hundreds of pathways and recommends optimized routes, including both known and novel pathways, demonstrating its effectiveness and potential for broader applications.

Biomedical researchers increasingly rely on large-scale structured databases for complex analytical tasks. However, current text-to-SQL systems often struggle to map qualitative scientific questions into executable SQL, particularly when implicit domain reasoning is required. We introduce BiomedSQL, the first benchmark explicitly designed to evaluate scientific reasoning in text-to-SQL generation over a real-world biomedical knowledge base. BiomedSQL comprises 68,000 question/SQL query/answer triples grounded in a harmonized BigQuery knowledge base that integrates gene-disease associations, causal inference from omics data, and drug approval records. Each question requires models to infer domain-specific criteria, such as genome-wide significance thresholds, effect directionality, or trial phase filtering, rather than rely on syntactic translation alone. We evaluate a range of open- and closed-source LLMs across prompting strategies and interaction paradigms. Our results reveal a substantial performance gap: GPT-o3-mini achieves 59.0% execution accuracy, while our custom multi-step agent, BMSQL, reaches 62.6%, both well below the expert baseline of 90.0%. BiomedSQL provides a new foundation for advancing text-to-SQL systems capable of supporting scientific discovery through robust reasoning over structured biomedical knowledge bases. Our dataset is publicly available at https://huggingface.co/datasets/NIH-CARD/BiomedSQL, and our code is open-source at https://github.com/NIH-CARD/biomedsql.

The challenge of replicating research results has posed a significant impediment to the field of molecular biology. The advent of modern intelligent systems has led to notable progress in various domains. Consequently, we embarked on an investigation of intelligent monitoring systems as a means of tackling the issue of the reproducibility crisis. Specifically, we first curate a comprehensive multimodal dataset, named ProBio, as an initial step towards this objective. This dataset comprises fine-grained hierarchical annotations intended for the purpose of studying activity understanding in BioLab. Next, we devise two challenging benchmarks, transparent solution tracking and multimodal action recognition, to emphasize the unique characteristics and difficulties associated with activity understanding in BioLab settings. Finally, we provide a thorough experimental evaluation of contemporary video understanding models and highlight their limitations in this specialized domain to identify potential avenues for future research. We hope ProBio with associated benchmarks may garner increased focus on modern AI techniques in the realm of molecular biology.

Understanding molecules is key to understanding organisms and driving advances in drug discovery, requiring interdisciplinary knowledge across chemistry and biology. Although large molecular language models have achieved notable success in interpreting molecular structures, their instruction datasets are limited to the specific knowledge from task-oriented datasets and do not fully cover the fundamental characteristics of molecules, hindering their abilities as general-purpose molecular assistants. To address this issue, we propose Mol-LLaMA, a large molecular language model that grasps the general knowledge centered on molecules via multi-modal instruction tuning. To this end, we design key data types that encompass the fundamental features of molecules, incorporating essential knowledge from molecular structures. In addition, to improve understanding of molecular features, we introduce a module that integrates complementary information from different molecular encoders, leveraging the distinct advantages of different molecular representations. Our experimental results demonstrate that Mol-LLaMA is capable of comprehending the general features of molecules and generating relevant responses to users' queries with detailed explanations, implying its potential as a general-purpose assistant for molecular analysis.

Aromaticity is a common chemical functionalities in bioactive molecules. In interstellar and circumstellar environments benzene and other small aromatics are considered the precursor for more complex prebiotic molecules and they have shown to potentially have rich ice-phase photochemistry. The availability of small organic molecules in prebiotic networks depends on their photostability in astrophysical environments preceding planet formation, particularly during the protoplanetary disk stage, as the disk composition is linked to the chemical make-up of planets and planetesimals. We study the ultraviolet (UV) photodestruction (120-160 nm) of five aromatic molecules in undiluted ices and, for selected cases, in astrophysically relevant ice matrices (H2O, CO, CO2). For each ice, we measure the destruction cross sections as a function of photon exposure. In undiluted ices, aromatic molecules exhibit substantially lower photodestruction cross sections (sigma < 10-19 cm2) than aliphatic hydrocarbons, including cyclohexane, (sigma = 2.8-4x10-18 cm2). Furthermore, neither substituent nature nor size affects the aromatic stability in pure ices, suggesting that the strong intermolecular interactions among aromatic molecules provide protection against VUV exposure, even with small to mid-sized ring substituents. In mixed ices, the photodestruction and reactivity of aromatic molecules (sigma = 2.5-6.1x10-18 cm2) increases by more than an order of magnitude, but are still lower than in the gas-phase. We attribute this to a weaker cage effect and matrix-specific interactions. We use the experimental photodestruction cross sections to estimate the lifetime of aromatic molecules in protoplanetary disks, denileating the disks regions in which aromatic photochemistry is expected to be the most active.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

Noise is a ubiquitous feature of the physical world. As a result, the first prerequisite of life is fault tolerance: maintaining integrity of state despite external bombardment. Recent experimental advances have revealed that biological systems achieve fault tolerance by implementing mathematically intricate error-correcting codes and by organizing in a modular fashion that physically separates functionally distinct subsystems. These elaborate structures represent a vanishing volume in the massive genetic configuration space. How is it possible that the primitive process of evolution, by which all biological systems evolved, achieved such unusual results? In this work, through experiments in Boolean networks, we show that the simultaneous presence of error correction and modularity in biological systems is no coincidence. Rather, it is a typical co-occurrence in noisy dynamic systems undergoing evolution. From this, we deduce the principle of error correction enhanced evolvability: systems possessing error-correcting codes are more effectively improved by evolution than those without.

Molecular representation is a foundational element in our understanding of the physical world. Its importance ranges from the fundamentals of chemical reactions to the design of new therapies and materials. Previous molecular machine learning models have employed strings, fingerprints, global features, and simple molecular graphs that are inherently information-sparse representations. However, as the complexity of prediction tasks increases, the molecular representation needs to encode higher fidelity information. This work introduces a novel approach to infusing quantum-chemical-rich information into molecular graphs via stereoelectronic effects. We show that the explicit addition of stereoelectronic interactions significantly improves the performance of molecular machine learning models. Furthermore, stereoelectronics-infused representations can be learned and deployed with a tailored double graph neural network workflow, enabling its application to any downstream molecular machine learning task. Finally, we show that the learned representations allow for facile stereoelectronic evaluation of previously intractable systems, such as entire proteins, opening new avenues of molecular design.

Many cellular processes involve information processing and decision making. We can probe these processes at increasing molecular detail. The analysis of heterogeneous data remains a challenge that requires new ways of thinking about cells in quantitative, predictive, and mechanistic ways. We discuss the role of mathematical models in the context of cell-fate decision making systems across the tree of life. Complex multi-cellular organisms have been a particular focus, but single celled organisms also have to sense and respond to their environment. We center our discussion around the idea of design principles which we can learn from observations and modeling, and exploit in order to (re)-design or guide cellular behavior.

The structure-function relationship is at the heart of biology and major protein deformations are correlated to specific functions. In the case of heme proteins, doming is associated with the respiratory function in hemoglobin and myoglobin, while ruffling has been correlated with electron transfer processes, such as in the case of Cytochrome c (Cyt c). The latter has indeed evolved to become an important electron transfer protein in humans. In its ferrous form, it undergoes ligand release and doming upon photoexcitation, but its ferric form does not release the distal ligand, while the return to the ground state has been attributed to thermal relaxation. Here, by combining femtosecond Fe K-edge X-ray absorption near-edge structure (XANES) studies and femtosecond Fe Kalpha and Kbeta X-ray emission spectroscopy (XES), we demonstrate that the photocycle of ferric Cyt c is entirely due to a cascade among excited spin states of the Iron ion, causing the ferric heme to undergo doming, which we identify for the first time. We also argue that this pattern is common to all ferric haems, raising the question of the biological relevance of doming in such proteins.

While artificial intelligence has made remarkable strides in revealing the relationship between biological macromolecules' primary sequence and tertiary structure, designing RNA sequences based on specified tertiary structures remains challenging. Though existing approaches in protein design have thoroughly explored structure-to-sequence dependencies in proteins, RNA design still confronts difficulties due to structural complexity and data scarcity. Moreover, direct transplantation of protein design methodologies into RNA design fails to achieve satisfactory outcomes although sharing similar structural components. In this study, we aim to systematically construct a data-driven RNA design pipeline. We crafted a large, well-curated benchmark dataset and designed a comprehensive structural modeling approach to represent the complex RNA tertiary structure. More importantly, we proposed a hierarchical data-efficient representation learning framework that learns structural representations through contrastive learning at both cluster-level and sample-level to fully leverage the limited data. By constraining data representations within a limited hyperspherical space, the intrinsic relationships between data points could be explicitly imposed. Moreover, we incorporated extracted secondary structures with base pairs as prior knowledge to facilitate the RNA design process. Extensive experiments demonstrate the effectiveness of our proposed method, providing a reliable baseline for future RNA design tasks. The source code and benchmark dataset are available at https://github.com/A4Bio/RDesign.

While deep learning has revolutionized the prediction of rigid protein structures, modelling the conformational ensembles of Intrinsically Disordered Proteins (IDPs) remains a key frontier. Current AI paradigms present a trade-off: Protein Language Models (PLMs) capture evolutionary statistics but lack explicit physical grounding, while generative models trained to model full ensembles are computationally expensive. In this work we critically assess these limits and propose a path forward. We introduce GeoGraph, a simulation-informed surrogate trained to predict ensemble-averaged statistics of residue-residue contact-map topology directly from sequence. By featurizing coarse-grained molecular dynamics simulations into residue- and sequence-level graph descriptors, we create a robust and information-rich learning target. Our evaluation demonstrates that this approach yields representations that are more predictive of key biophysical properties than existing methods.

Motivation: Biomedical knowledge graphs (KGs) are crucial for drug discovery and disease understanding, yet their completion and reasoning are challenging. Knowledge Embedding (KE) methods capture global semantics but struggle with dynamic structural integration, while Graph Neural Networks (GNNs) excel locally but often lack semantic understanding. Even ensemble approaches, including those leveraging language models, often fail to achieve a deep, adaptive, and synergistic co-evolution between semantic comprehension and structural learning. Addressing this critical gap in fostering continuous, reciprocal refinement between these two aspects in complex biomedical KGs is paramount. Results: We introduce BioGraphFusion, a novel framework for deeply synergistic semantic and structural learning. BioGraphFusion establishes a global semantic foundation via tensor decomposition, guiding an LSTM-driven mechanism to dynamically refine relation embeddings during graph propagation. This fosters adaptive interplay between semantic understanding and structural learning, further enhanced by query-guided subgraph construction and a hybrid scoring mechanism. Experiments across three key biomedical tasks demonstrate BioGraphFusion's superior performance over state-of-the-art KE, GNN, and ensemble models. A case study on Cutaneous Malignant Melanoma 1 (CMM1) highlights its ability to unveil biologically meaningful pathways. Availability and Implementation: Source code and all training data are freely available for download at https://github.com/Y-TARL/BioGraphFusion. Supplementary information: Supplementary data are available at Bioinformatics online.

Large language models (LLMs) and vision-language models (VLMs) have the potential to transform biological research by enabling autonomous experimentation. Yet, their application remains constrained by rigid protocol design, limited adaptability to dynamic lab conditions, inadequate error handling, and high operational complexity. Here we introduce BioMARS (Biological Multi-Agent Robotic System), an intelligent platform that integrates LLMs, VLMs, and modular robotics to autonomously design, plan, and execute biological experiments. BioMARS uses a hierarchical architecture: the Biologist Agent synthesizes protocols via retrieval-augmented generation; the Technician Agent translates them into executable robotic pseudo-code; and the Inspector Agent ensures procedural integrity through multimodal perception and anomaly detection. The system autonomously conducts cell passaging and culture tasks, matching or exceeding manual performance in viability, consistency, and morphological integrity. It also supports context-aware optimization, outperforming conventional strategies in differentiating retinal pigment epithelial cells. A web interface enables real-time human-AI collaboration, while a modular backend allows scalable integration with laboratory hardware. These results highlight the feasibility of generalizable, AI-driven laboratory automation and the transformative role of language-based reasoning in biological research.

Understanding the biological mechanism of disease is critical for medicine, and in particular drug discovery. AI-powered analysis of genome-scale biological data hold great potential in this regard. The increasing availability of single-cell RNA sequencing data has enabled the development of large foundation models for disease biology. However, existing foundation models either do not improve or only modestly improve over task-specific models in downstream applications. Here, we explored two avenues for improving the state-of-the-art. First, we scaled the pre-training dataset to 116 million cells, which is larger than those used by previous models. Second, we leveraged the availability of large-scale biological annotations as a form of supervision during pre-training. We trained the TEDDY family of models comprising six transformer-based state-of-the-art single-cell foundation models with 70 million, 160 million, and 400 million parameters. We vetted our models on two downstream evaluation tasks -- identifying the underlying disease state of held-out donors not seen during training and distinguishing healthy cells from diseased ones for disease conditions and donors not seen during training. Scaling experiments showed that performance improved predictably with both data volume and parameter count. Our models showed substantial improvement over existing work on the first task and more muted improvements on the second.

Computing in the life sciences has undergone a transformative evolution, from early computational models in the 1950s to the applications of artificial intelligence (AI) and machine learning (ML) seen today. This paper highlights key milestones and technological advancements through the historical development of computing in the life sciences. The discussion includes the inception of computational models for biological processes, the advent of bioinformatics tools, and the integration of AI/ML in modern life sciences research. Attention is given to AI-enabled tools used in the life sciences, such as scientific large language models and bio-AI tools, examining their capabilities, limitations, and impact to biological risk. This paper seeks to clarify and establish essential terminology and concepts to ensure informed decision-making and effective communication across disciplines.

The recent success of large foundation models in artificial intelligence has prompted the emergence of chemical pre-trained models. Despite the growing interest in large molecular pre-trained models that provide informative representations for downstream tasks, attempts for multimodal pre-training approaches on the molecule domain were limited. To address this, we present a novel multimodal molecular pre-trained model that incorporates the modalities of structure and biochemical properties, drawing inspiration from recent advances in multimodal learning techniques. Our proposed model pipeline of data handling and training objectives aligns the structure/property features in a common embedding space, which enables the model to regard bidirectional information between the molecules' structure and properties. These contributions emerge synergistic knowledge, allowing us to tackle both multimodal and unimodal downstream tasks through a single model. Through extensive experiments, we demonstrate that our model shows remarkable capabilities in solving various meaningful chemical challenges, including conditional molecule generation, property prediction, molecule classification, and reaction prediction.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

Biological protocols are fundamental to reproducible and safe life science research. While LLMs excel on general tasks, their systematic evaluation on these highly specialized, accuracy-critical, and inherently procedural texts remains limited. In this work, we present BioProBench, the first large-scale, integrated multi-task benchmark for biological protocol understanding and reasoning. While limited benchmarks have touched upon specific aspects like protocol QA, BioProBench provides a comprehensive suite of five core tasks: Protocol Question Answering, Step Ordering, Error Correction, Protocol Generation, and Protocol Reasoning, enabling a holistic evaluation of LLMs on procedural biological texts. Built upon 27K original protocols, it yields nearly 556K high-quality structured instances. We evaluate 12 mainstream open/closed-source LLMs on BioProBench. Experimental results reveal that while top models preform well on surface understanding tasks, struggle significantly with deep reasoning and structured generation tasks like ordering and generation. Furthermore, model comparisons reveal diverse performance: certain open-source models approach closed-source levels on some tasks, yet bio-specific small models lag behind general LLMs, indicating limitations on complex procedural content. Overall, our findings underscore that procedural reasoning within biological protocols represents a significant challenge for current LLMs. BioProBench serves as a standardized framework to diagnose these specific limitations and guide the development of AI systems better equipped for safely automating complex scientific procedures. The code and data are available at: https://github.com/YuyangSunshine/bioprotocolbench and https://huggingface.co/datasets/GreatCaptainNemo/BioProBench.

Biological processes, functions, and properties are intricately linked to the ensemble of protein conformations, rather than being solely determined by a single stable conformation. In this study, we have developed P2DFlow, a generative model based on SE(3) flow matching, to predict the structural ensembles of proteins. We specifically designed a valuable prior for the flow process and enhanced the model's ability to distinguish each intermediate state by incorporating an additional dimension to describe the ensemble data, which can reflect the physical laws governing the distribution of ensembles, so that the prior knowledge can effectively guide the generation process. When trained and evaluated on the MD datasets of ATLAS, P2DFlow outperforms other baseline models on extensive experiments, successfully capturing the observable dynamic fluctuations as evidenced in crystal structure and MD simulations. As a potential proxy agent for protein molecular simulation, the high-quality ensembles generated by P2DFlow could significantly aid in understanding protein functions across various scenarios. Code is available at https://github.com/BLEACH366/P2DFlow

Language models for biological and chemical sequences enable crucial applications such as drug discovery, protein engineering, and precision medicine. Currently, these language models are predominantly based on Transformer architectures. While Transformers have yielded impressive results, their quadratic runtime dependency on the sequence length complicates their use for long genomic sequences and in-context learning on proteins and chemical sequences. Recently, the recurrent xLSTM architecture has been shown to perform favorably compared to Transformers and modern state-space model (SSM) architectures in the natural language domain. Similar to SSMs, xLSTMs have a linear runtime dependency on the sequence length and allow for constant-memory decoding at inference time, which makes them prime candidates for modeling long-range dependencies in biological and chemical sequences. In this work, we tailor xLSTM towards these domains and propose a suite of architectural variants called Bio-xLSTM. Extensive experiments in three large domains, genomics, proteins, and chemistry, were performed to assess xLSTM's ability to model biological and chemical sequences. The results show that models based on Bio-xLSTM a) can serve as proficient generative models for DNA, protein, and chemical sequences, b) learn rich representations for those modalities, and c) can perform in-context learning for proteins and small molecules.

Complex cell signaling systems -- governed by varying protein abundances and interactions -- generate diverse cell types across organs. These systems evolve under influences such as age, sex, diet, environmental exposures, and diseases, making them challenging to decode given the involvement of tens of thousands of genes and proteins. Recently, hundreds of millions of single-cell omics data have provided a robust foundation for understanding these signaling networks within various cell subpopulations and conditions. Inspired by the success of large foundation models (for example, large language models and large vision models) pre-trained on massive datasets, we introduce OmniCellTOSG, the first dataset of cell text-omic signaling graphs (TOSGs). Each TOSG represents the signaling network of an individual or meta-cell and is labeled with information such as organ, disease, sex, age, and cell subtype. OmniCellTOSG offers two key contributions. First, it introduces a novel graph model that integrates human-readable annotations -- such as biological functions, cellular locations, signaling pathways, related diseases, and drugs -- with quantitative gene and protein abundance data, enabling graph reasoning to decode cell signaling. This approach calls for new joint models combining large language models and graph neural networks. Second, the dataset is built from single-cell RNA sequencing data of approximately 120 million cells from diverse tissues and conditions (healthy and diseased) and is fully compatible with PyTorch. This facilitates the development of innovative cell signaling models that could transform research in life sciences, healthcare, and precision medicine. The OmniCellTOSG dataset is continuously expanding and will be updated regularly. The dataset and code are available at https://github.com/FuhaiLiAiLab/OmniCellTOSG.

Proteins are essential biological macromolecules that execute life functions. Local motifs within protein structures, such as active sites, are the most critical components for linking structure to function and are key to understanding protein evolution and enabling protein engineering. Existing computational methods struggle to identify and compare these local structures, which leaves a significant gap in understanding protein structures and harnessing their functions. This study presents PLASMA, the first deep learning framework for efficient and interpretable residue-level protein substructure alignment. We reformulate the problem as a regularized optimal transport task and leverage differentiable Sinkhorn iterations. For a pair of input protein structures, PLASMA outputs a clear alignment matrix with an interpretable overall similarity score. Through extensive quantitative evaluations and three biological case studies, we demonstrate that PLASMA achieves accurate, lightweight, and interpretable residue-level alignment. Additionally, we introduce PLASMA-PF, a training-free variant that provides a practical alternative when training data are unavailable. Our method addresses a critical gap in protein structure analysis tools and offers new opportunities for functional annotation, evolutionary studies, and structure-based drug design. Reproducibility is ensured via our official implementation at https://github.com/ZW471/PLASMA-Protein-Local-Alignment.git.

Nanobodies, single-domain antibody fragments derived from camelid heavy-chain-only antibodies, exhibit unique advantages such as compact size, high stability, and strong binding affinity, making them valuable tools in therapeutics and diagnostics. While recent advances in pretrained protein and antibody language models (PPLMs and PALMs) have greatly enhanced biomolecular understanding, nanobody-specific modeling remains underexplored and lacks a unified benchmark. To address this gap, we introduce NbBench, the first comprehensive benchmark suite for nanobody representation learning. Spanning eight biologically meaningful tasks across nine curated datasets, NbBench encompasses structure annotation, binding prediction, and developability assessment. We systematically evaluate eleven representative models--including general-purpose protein LMs, antibody-specific LMs, and nanobody-specific LMs--in a frozen setting. Our analysis reveals that antibody language models excel in antigen-related tasks, while performance on regression tasks such as thermostability and affinity remains challenging across all models. Notably, no single model consistently outperforms others across all tasks. By standardizing datasets, task definitions, and evaluation protocols, NbBench offers a reproducible foundation for assessing and advancing nanobody modeling.

Biomedical knowledge graphs (BioMedKGs) are essential infrastructures for biomedical and healthcare big data and artificial intelligence (AI), facilitating natural language processing, model development, and data exchange. For decades, these knowledge graphs have been developed via expert curation; however, this method can no longer keep up with today's AI development, and a transition to algorithmically generated BioMedKGs is necessary. In this work, we introduce the Biomedical Informatics Ontology System (BIOS), the first large-scale publicly available BioMedKG generated completely by machine learning algorithms. BIOS currently contains 4.1 million concepts, 7.4 million terms in two languages, and 7.3 million relation triplets. We present the methodology for developing BIOS, including the curation of raw biomedical terms, computational identification of synonymous terms and aggregation of these terms to create concept nodes, semantic type classification of the concepts, relation identification, and biomedical machine translation. We provide statistics on the current BIOS content and perform preliminary assessments of term quality, synonym grouping, and relation extraction. The results suggest that machine learning-based BioMedKG development is a viable alternative to traditional expert curation.

Recent advancements in protein structure determination are revolutionizing our understanding of proteins. Still, a significant gap remains in the availability of comprehensive datasets that focus on the dynamics of proteins, which are crucial for understanding protein function, folding, and interactions. To address this critical gap, we introduce mdCATH, a dataset generated through an extensive set of all-atom molecular dynamics simulations of a diverse and representative collection of protein domains. This dataset comprises all-atom systems for 5,398 domains, modeled with a state-of-the-art classical force field, and simulated in five replicates each at five temperatures from 320 K to 413 K. The mdCATH dataset records coordinates and forces every 1 ns, for over 62 ms of accumulated simulation time, effectively capturing the dynamics of the various classes of domains and providing a unique resource for proteome-wide statistical analyses of protein unfolding thermodynamics and kinetics. We outline the dataset structure and showcase its potential through four easily reproducible case studies, highlighting its capabilities in advancing protein science.

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

The transformer architecture has revolutionized bioinformatics and driven progress in the understanding and prediction of the properties of biomolecules. Almost all research on large-scale biosequence transformers has focused on one domain at a time (single-omic), usually nucleotides or peptides. These models have seen incredible success in downstream tasks in each domain and have achieved particularly noteworthy breakthroughs in sequences of peptides and structural modeling. However, these single-omic models are naturally incapable of modeling multi-omic tasks, one of the most biologically critical being nucleotide-peptide interactions. We present our work training the first multi-omic nucleotide-peptide foundation models. We show that these multi-omic models (MOMs) can learn joint representations between various single-omic distributions that are emergently consistent with the Central Dogma of molecular biology, despite only being trained on unlabeled biosequences. We further demonstrate that MOMs can be fine-tuned to achieve state-of-the-art results on peptide-nucleotide interaction tasks, namely predicting the change in Gibbs free energy ({\Delta}G) of the binding interaction between a given oligonucleotide and peptide, as well as the effect on this binding interaction due to mutations in the oligonucleotide sequence ({\Delta}{\Delta}G). Remarkably, we show that multi-omic biosequence transformers emergently learn useful structural information without any prior structural training, allowing us to predict which peptide residues are most involved in the peptide-nucleotide binding interaction. Lastly, we provide evidence that multi-omic biosequence models are non-inferior to foundation models trained on single-omics distributions, suggesting a more generalized or foundational approach to building these models.

Proteins perform nearly all cellular functions and constitute most drug targets, making their analysis fundamental to understanding human biology in health and disease. Tandem mass spectrometry (MS^2) is the major analytical technique in proteomics that identifies peptides by ionizing them, fragmenting them, and using the resulting mass spectra to identify and quantify proteins in biological samples. In MS^2 analysis, peptide fragment ion probability prediction plays a critical role, enhancing the accuracy of peptide identification from mass spectra as a complement to the intensity information. Current approaches rely on global statistics of fragmentation, which assumes that a fragment's probability is uniform across all peptides. Nevertheless, this assumption is oversimplified from a biochemical principle point of view and limits accurate prediction. To address this gap, we present Pep2Prob, the first comprehensive dataset and benchmark designed for peptide-specific fragment ion probability prediction. The proposed dataset contains fragment ion probability statistics for 608,780 unique precursors (each precursor is a pair of peptide sequence and charge state), summarized from more than 183 million high-quality, high-resolution, HCD MS^2 spectra with validated peptide assignments and fragmentation annotations. We establish baseline performance using simple statistical rules and learning-based methods, and find that models leveraging peptide-specific information significantly outperform previous methods using only global fragmentation statistics. Furthermore, performance across benchmark models with increasing capacities suggests that the peptide-fragmentation relationship exhibits complex nonlinearities requiring sophisticated machine learning approaches.

Understanding biological processes, drug development, and biotechnological advancements requires detailed analysis of protein structures and sequences, a task in protein research that is inherently complex and time-consuming when performed manually. To streamline this process, we introduce ProteinGPT, a state-of-the-art multi-modal protein chat system, that allows users to upload protein sequences and/or structures for comprehensive protein analysis and responsive inquiries. ProteinGPT seamlessly integrates protein sequence and structure encoders with linear projection layers for precise representation adaptation, coupled with a large language model (LLM) to generate accurate and contextually relevant responses. To train ProteinGPT, we construct a large-scale dataset of 132,092 proteins with annotations, and optimize the instruction-tuning process using GPT-4o. This innovative system ensures accurate alignment between the user-uploaded data and prompts, simplifying protein analysis. Experiments show that ProteinGPT can produce promising responses to proteins and their corresponding questions.

Developing therapeutics is a lengthy and expensive process that requires the satisfaction of many different criteria, and AI models capable of expediting the process would be invaluable. However, the majority of current AI approaches address only a narrowly defined set of tasks, often circumscribed within a particular domain. To bridge this gap, we introduce Tx-LLM, a generalist large language model (LLM) fine-tuned from PaLM-2 which encodes knowledge about diverse therapeutic modalities. Tx-LLM is trained using a collection of 709 datasets that target 66 tasks spanning various stages of the drug discovery pipeline. Using a single set of weights, Tx-LLM simultaneously processes a wide variety of chemical or biological entities(small molecules, proteins, nucleic acids, cell lines, diseases) interleaved with free-text, allowing it to predict a broad range of associated properties, achieving competitive with state-of-the-art (SOTA) performance on 43 out of 66 tasks and exceeding SOTA on 22. Among these, Tx-LLM is particularly powerful and exceeds best-in-class performance on average for tasks combining molecular SMILES representations with text such as cell line names or disease names, likely due to context learned during pretraining. We observe evidence of positive transfer between tasks with diverse drug types (e.g.,tasks involving small molecules and tasks involving proteins), and we study the impact of model size, domain finetuning, and prompting strategies on performance. We believe Tx-LLM represents an important step towards LLMs encoding biochemical knowledge and could have a future role as an end-to-end tool across the drug discovery development pipeline.

The integration of molecule and language has garnered increasing attention in molecular science. Recent advancements in Language Models (LMs) have demonstrated potential for the comprehensive modeling of molecule and language. However, existing works exhibit notable limitations. Most existing works overlook the modeling of 3D information, which is crucial for understanding molecular structures and also functions. While some attempts have been made to leverage external structure encoding modules to inject the 3D molecular information into LMs, there exist obvious difficulties that hinder the integration of molecular structure and language text, such as modality alignment and separate tuning. To bridge this gap, we propose 3D-MolT5, a unified framework designed to model both 1D molecular sequence and 3D molecular structure. The key innovation lies in our methodology for mapping fine-grained 3D substructure representations (based on 3D molecular fingerprints) to a specialized 3D token vocabulary for 3D-MolT5. This 3D structure token vocabulary enables the seamless combination of 1D sequence and 3D structure representations in a tokenized format, allowing 3D-MolT5 to encode molecular sequence (SELFIES), molecular structure, and text sequences within a unified architecture. Alongside, we further introduce 1D and 3D joint pre-training to enhance the model's comprehension of these diverse modalities in a joint representation space and better generalize to various tasks for our foundation model. Through instruction tuning on multiple downstream datasets, our proposed 3D-MolT5 shows superior performance than existing methods in molecular property prediction, molecule captioning, and text-based molecule generation tasks. Our code will be available on GitHub soon.

In molecular research, simulation \& design of molecules are key areas with significant implications for drug development, material science, and other fields. Current classical computational power falls inadequate to simulate any more than small molecules, let alone protein chains on hundreds of peptide. Therefore these experiment are done physically in wet-lab, but it takes a lot of time \& not possible to examine every molecule due to the size of the search area, tens of billions of dollars are spent every year in these research experiments. Molecule simulation \& design has lately advanced significantly by machine learning models, A fresh perspective on the issue of chemical synthesis is provided by deep generative models for graph-structured data. By optimising differentiable models that produce molecular graphs directly, it is feasible to avoid costly search techniques in the discrete and huge space of chemical structures. But these models also suffer from computational limitations when dimensions become huge and consume huge amount of resources. Quantum Generative machine learning in recent years have shown some empirical results promising significant advantages over classical counterparts.

Scientific Large Language Models (Sci-LLMs) have emerged as a promising frontier for accelerating biological discovery. However, these models face a fundamental challenge when processing raw biomolecular sequences: the tokenization dilemma. Whether treating sequences as a specialized language, risking the loss of functional motif information, or as a separate modality, introducing formidable alignment challenges, current strategies fundamentally limit their reasoning capacity. We challenge this sequence-centric paradigm by positing that a more effective strategy is to provide Sci-LLMs with high-level structured context derived from established bioinformatics tools, thereby bypassing the need to interpret low-level noisy sequence data directly. Through a systematic comparison of leading Sci-LLMs on biological reasoning tasks, we tested three input modes: sequence-only, context-only, and a combination of both. Our findings are striking: the context-only approach consistently and substantially outperforms all other modes. Even more revealing, the inclusion of the raw sequence alongside its high-level context consistently degrades performance, indicating that raw sequences act as informational noise, even for models with specialized tokenization schemes. These results suggest that the primary strength of existing Sci-LLMs lies not in their nascent ability to interpret biomolecular syntax from scratch, but in their profound capacity for reasoning over structured, human-readable knowledge. Therefore, we argue for reframing Sci-LLMs not as sequence decoders, but as powerful reasoning engines over expert knowledge. This work lays the foundation for a new class of hybrid scientific AI agents, repositioning the developmental focus from direct sequence interpretation towards high-level knowledge synthesis. The code is available at https://github.com/opendatalab-raiser/CoKE.

Designing de novo proteins beyond those found in nature holds significant promise for advancements in both scientific and engineering applications. Current methodologies for protein design often rely on AI-based models, such as surrogate models that address end-to-end problems by linking protein structure to material properties or vice versa. However, these models frequently focus on specific material objectives or structural properties, limiting their flexibility when incorporating out-of-domain knowledge into the design process or comprehensive data analysis is required. In this study, we introduce ProtAgents, a platform for de novo protein design based on Large Language Models (LLMs), where multiple AI agents with distinct capabilities collaboratively address complex tasks within a dynamic environment. The versatility in agent development allows for expertise in diverse domains, including knowledge retrieval, protein structure analysis, physics-based simulations, and results analysis. The dynamic collaboration between agents, empowered by LLMs, provides a versatile approach to tackling protein design and analysis problems, as demonstrated through diverse examples in this study. The problems of interest encompass designing new proteins, analyzing protein structures and obtaining new first-principles data -- natural vibrational frequencies -- via physics simulations. The concerted effort of the system allows for powerful automated and synergistic design of de novo proteins with targeted mechanical properties. The flexibility in designing the agents, on one hand, and their capacity in autonomous collaboration through the dynamic LLM-based multi-agent environment on the other hand, unleashes great potentials of LLMs in addressing multi-objective materials problems and opens up new avenues for autonomous materials discovery and design.

Large language models have already demonstrated their formidable capabilities in general domains, ushering in a revolutionary transformation. However, exploring and exploiting the extensive knowledge of these models to comprehend multi-omics biology remains underexplored. To fill this research gap, we first introduce Biology-Instructions, the first large-scale multi-omics biological sequences-related instruction-tuning dataset including DNA, RNA, proteins, and multi-molecules, designed to bridge the gap between large language models (LLMs) and complex biological sequences-related tasks. This dataset can enhance the versatility of LLMs by integrating diverse biological sequenced-based prediction tasks with advanced reasoning capabilities, while maintaining conversational fluency. Additionally, we reveal significant performance limitations in even state-of-the-art LLMs on biological sequence-related multi-omics tasks without specialized pre-training and instruction-tuning. We further develop a strong baseline called ChatMultiOmics with a novel three-stage training pipeline, demonstrating the powerful ability to understand biology by using Biology-Instructions. Biology-Instructions and ChatMultiOmics are publicly available and crucial resources for enabling more effective integration of LLMs with multi-omics sequence analysis.

Computational design of protein-binding proteins is a fundamental capability with broad utility in biomedical research and biotechnology. Recent methods have made strides against some target proteins, but on-demand creation of high-affinity binders without multiple rounds of experimental testing remains an unsolved challenge. This technical report introduces AlphaProteo, a family of machine learning models for protein design, and details its performance on the de novo binder design problem. With AlphaProteo, we achieve 3- to 300-fold better binding affinities and higher experimental success rates than the best existing methods on seven target proteins. Our results suggest that AlphaProteo can generate binders "ready-to-use" for many research applications using only one round of medium-throughput screening and no further optimization.

Antibodies comprise the most versatile class of binding molecules, with numerous applications in biomedicine. Computational design of antibodies involves generating novel and diverse sequences, while maintaining structural consistency. Unique to antibodies, designing the complementarity-determining region (CDR), which determines the antigen binding affinity and specificity, creates its own unique challenges. Recent deep learning models have shown impressive results, however the limited number of known antibody sequence/structure pairs frequently leads to degraded performance, particularly lacking diversity in the generated sequences. In our work we address this challenge by leveraging Model Reprogramming (MR), which repurposes pretrained models on a source language to adapt to the tasks that are in a different language and have scarce data - where it may be difficult to train a high-performing model from scratch or effectively fine-tune an existing pre-trained model on the specific task. Specifically, we introduce ReprogBert in which a pretrained English language model is repurposed for protein sequence infilling - thus considers cross-language adaptation using less data. Results on antibody design benchmarks show that our model on low-resourced antibody sequence dataset provides highly diverse CDR sequences, up to more than a two-fold increase of diversity over the baselines, without losing structural integrity and naturalness. The generated sequences also demonstrate enhanced antigen binding specificity and virus neutralization ability. Code is available at https://github.com/IBM/ReprogBERT

Generative machine learning models are increasingly being used to design novel proteins for therapeutic and biotechnological applications. However, the current methods mostly focus on the design of proteins with a fixed backbone structure, which leads to their limited ability to account for protein flexibility, one of the crucial properties for protein function. Learning to engineer protein flexibility is problematic because the available data are scarce, heterogeneous, and costly to obtain using computational as well as experimental methods. Our contributions to address this problem are three-fold. First, we comprehensively compare methods for quantifying protein flexibility and identify data relevant to learning. Second, we design and train flexibility predictors utilizing sequential or both sequential and structural information on the input. We overcome the data scarcity issue by leveraging a pre-trained protein language model. Third, we introduce a method for fine-tuning a protein inverse folding model to steer it toward desired flexibility in specified regions. We demonstrate that our method Flexpert-Design enables guidance of inverse folding models toward increased flexibility. This opens up new possibilities for protein flexibility engineering and the development of proteins with enhanced biological activities.

Networks provide a powerful formalism for modeling complex systems by using a model of pairwise interactions. But much of the structure within these systems involves interactions that take place among more than two nodes at once; for example, communication within a group rather than person-to person, collaboration among a team rather than a pair of coauthors, or biological interaction between a set of molecules rather than just two. Such higher-order interactions are ubiquitous, but their empirical study has received limited attention, and little is known about possible organizational principles of such structures. Here we study the temporal evolution of 19 datasets with explicit accounting for higher-order interactions. We show that there is a rich variety of structure in our datasets but datasets from the same system types have consistent patterns of higher-order structure. Furthermore, we find that tie strength and edge density are competing positive indicators of higher-order organization, and these trends are consistent across interactions involving differing numbers of nodes. To systematically further the study of theories for such higher-order structures, we propose higher-order link prediction as a benchmark problem to assess models and algorithms that predict higher-order structure. We find a fundamental differences from traditional pairwise link prediction, with a greater role for local rather than long-range information in predicting the appearance of new interactions.

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs, as well as providing structure-aware representations for predictive tasks.

In recent years, protein-text models have gained significant attention for their potential in protein generation and understanding. Current approaches focus on integrating protein-related knowledge into large language models through continued pretraining and multi-modal alignment, enabling simultaneous comprehension of textual descriptions and protein sequences. Through a thorough analysis of existing model architectures and text-based protein understanding benchmarks, we identify significant data leakage issues present in current benchmarks. Moreover, conventional metrics derived from natural language processing fail to accurately assess the model's performance in this domain. To address these limitations, we reorganize existing datasets and introduce a novel evaluation framework based on biological entities. Motivated by our observation, we propose a retrieval-enhanced method, which significantly outperforms fine-tuned LLMs for protein-to-text generation and shows accuracy and efficiency in training-free scenarios. Our code and data can be seen at https://github.com/IDEA-XL/RAPM.

Interrogating the evolution of biological changes at early stages of life requires longitudinal profiling of molecules, such as DNA methylation, which can be challenging with children. We introduce a probabilistic and longitudinal machine learning framework based on multi-mean Gaussian processes (GPs), accounting for individual and gene correlations across time. This method provides future predictions of DNA methylation status at different individual ages while accounting for uncertainty. Our model is trained on a birth cohort of children with methylation profiled at ages 0-4, and we demonstrated that the status of methylation sites for each child can be accurately predicted at ages 5-7. We show that methylation profiles predicted by multi-mean GPs can be used to estimate other phenotypes, such as epigenetic age, and enable comparison to other health measures of interest. This approach encourages epigenetic studies to move towards longitudinal design for investigating epigenetic changes during development, ageing and disease progression.

Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language Models (pLMs) aim to unlock insights from the vast space of unlabeled protein sequences by learning rich, semantic representations from primary sequences via masked language modeling. However, these models typically exhibit limited generative capacity. In this work, we introduce the Diffusion Sequence Model (DSM), a novel pLM trained with masked diffusion to enable both high-quality representation learning and generative protein design. DSM builds upon the ESM2 architecture by incorporating a masked forward diffusion process inspired by the LLaDA framework. After training, DSM is capable of generating diverse, biomimetic sequences that align with expected amino acid compositions, secondary structures, and predicted functions, even with 90\% token corruption. Furthermore, DSM's learned representations match or exceed those of similarly sized pLMs on downstream tasks. We also introduce DSM(ppi), a variant fine-tuned to generate protein binders by attending to target sequences. We demonstrate DSM(ppi)'s effectiveness on the challenging Bench-tested Binder Benchmark (BenchBB), where both DSM and DSM(ppi) produce candidates with superior predicted binding affinity compared to known binders. Our results establish masked diffusion as a powerful paradigm for unifying protein representation and generation in a single framework.

Understanding the various properties of glycans with machine learning has shown some preliminary promise. However, previous methods mainly focused on modeling the backbone structure of glycans as graphs of monosaccharides (i.e., sugar units), while they neglected the atomic structures underlying each monosaccharide, which are actually important indicators of glycan properties. We fill this blank by introducing the GlycanAA model for All-Atom-wise Glycan modeling. GlycanAA models a glycan as a heterogeneous graph with monosaccharide nodes representing its global backbone structure and atom nodes representing its local atomic-level structures. Based on such a graph, GlycanAA performs hierarchical message passing to capture from local atomic-level interactions to global monosaccharide-level interactions. To further enhance model capability, we pre-train GlycanAA on a high-quality unlabeled glycan dataset, deriving the PreGlycanAA model. We design a multi-scale mask prediction algorithm to endow the model about different levels of dependencies in a glycan. Extensive benchmark results show the superiority of GlycanAA over existing glycan encoders and verify the further improvements achieved by PreGlycanAA. We maintain all resources at https://github.com/kasawa1234/GlycanAA

Identifying drug-target interactions is essential for developing effective therapeutics. Binding affinity quantifies these interactions, and traditional approaches rely on computationally intensive 3D structural data. In contrast, language models can efficiently process sequential data, offering an alternative approach to molecular representation. In the current study, we introduce BAPULM, an innovative sequence-based framework that leverages the chemical latent representations of proteins via ProtT5-XL-U50 and ligands through MolFormer, eliminating reliance on complex 3D configurations. Our approach was validated extensively on benchmark datasets, achieving scoring power (R) values of 0.925 pm 0.043, 0.914 pm 0.004, and 0.8132 pm 0.001 on benchmark1k2101, Test2016_290, and CSAR-HiQ_36, respectively. These findings indicate the robustness and accuracy of BAPULM across diverse datasets and underscore the potential of sequence-based models in-silico drug discovery, offering a scalable alternative to 3D-centric methods for screening potential ligands.

We present an approach of using AI to model and simulate biology and life. Why is it important? Because at the core of medicine, pharmacy, public health, longevity, agriculture and food security, environmental protection, and clean energy, it is biology at work. Biology in the physical world is too complex to manipulate and always expensive and risky to tamper with. In this perspective, we layout an engineering viable approach to address this challenge by constructing an AI-Driven Digital Organism (AIDO), a system of integrated multiscale foundation models, in a modular, connectable, and holistic fashion to reflect biological scales, connectedness, and complexities. An AIDO opens up a safe, affordable and high-throughput alternative platform for predicting, simulating and programming biology at all levels from molecules to cells to individuals. We envision that an AIDO is poised to trigger a new wave of better-guided wet-lab experimentation and better-informed first-principle reasoning, which can eventually help us better decode and improve life.

Understanding the relationships between protein sequence, structure and function is a long-standing biological challenge with manifold implications from drug design to our understanding of evolution. Recently, protein language models have emerged as the preferred method for this challenge, thanks to their ability to harness large sequence databases. Yet, their reliance on expansive sequence data and parameter sets limits their flexibility and practicality in real-world scenarios. Concurrently, the recent surge in computationally predicted protein structures unlocks new opportunities in protein representation learning. While promising, the computational burden carried by such complex data still hinders widely-adopted practical applications. To address these limitations, we introduce a novel framework that enhances protein language models by integrating protein structural data. Drawing from recent advances in graph transformers, our approach refines the self-attention mechanisms of pretrained language transformers by integrating structural information with structure extractor modules. This refined model, termed Protein Structure Transformer (PST), is further pretrained on a small protein structure database, using the same masked language modeling objective as traditional protein language models. Empirical evaluations of PST demonstrate its superior parameter efficiency relative to protein language models, despite being pretrained on a dataset comprising only 542K structures. Notably, PST consistently outperforms the state-of-the-art foundation model for protein sequences, ESM-2, setting a new benchmark in protein function prediction. Our findings underscore the potential of integrating structural information into protein language models, paving the way for more effective and efficient protein modeling Code and pretrained models are available at https://github.com/BorgwardtLab/PST.

Accurately classifying chemical structures is essential for cheminformatics and bioinformatics, including tasks such as identifying bioactive compounds of interest, screening molecules for toxicity to humans, finding non-organic compounds with desirable material properties, or organizing large chemical libraries for drug discovery or environmental monitoring. However, manual classification is labor-intensive and difficult to scale to large chemical databases. Existing automated approaches either rely on manually constructed classification rules, or the use of deep learning methods that lack explainability. This work presents an approach that uses generative artificial intelligence to automatically write chemical classifier programs for classes in the Chemical Entities of Biological Interest (ChEBI) database. These programs can be used for efficient deterministic run-time classification of SMILES structures, with natural language explanations. The programs themselves constitute an explainable computable ontological model of chemical class nomenclature, which we call the ChEBI Chemical Class Program Ontology (C3PO). We validated our approach against the ChEBI database, and compared our results against state of the art deep learning models. We also demonstrate the use of C3PO to classify out-of-distribution examples taken from metabolomics repositories and natural product databases. We also demonstrate the potential use of our approach to find systematic classification errors in existing chemical databases, and show how an ensemble artificial intelligence approach combining generated ontologies, automated literature search, and multimodal vision models can be used to pinpoint potential errors requiring expert validation

In the development of science, accurate and reproducible documentation of the experimental process is crucial. Automatic recognition of the actions in experiments from videos would help experimenters by complementing the recording of experiments. Towards this goal, we propose FineBio, a new fine-grained video dataset of people performing biological experiments. The dataset consists of multi-view videos of 32 participants performing mock biological experiments with a total duration of 14.5 hours. One experiment forms a hierarchical structure, where a protocol consists of several steps, each further decomposed into a set of atomic operations. The uniqueness of biological experiments is that while they require strict adherence to steps described in each protocol, there is freedom in the order of atomic operations. We provide hierarchical annotation on protocols, steps, atomic operations, object locations, and their manipulation states, providing new challenges for structured activity understanding and hand-object interaction recognition. To find out challenges on activity understanding in biological experiments, we introduce baseline models and results on four different tasks, including (i) step segmentation, (ii) atomic operation detection (iii) object detection, and (iv) manipulated/affected object detection. Dataset and code are available from https://github.com/aistairc/FineBio.

Machine learning (ML) models hold the promise of transforming atomic simulations by delivering quantum chemical accuracy at a fraction of the computational cost. Realization of this potential would enable high-throughout, high-accuracy molecular screening campaigns to explore vast regions of chemical space and facilitate ab initio simulations at sizes and time scales that were previously inaccessible. However, a fundamental challenge to creating ML models that perform well across molecular chemistry is the lack of comprehensive data for training. Despite substantial efforts in data generation, no large-scale molecular dataset exists that combines broad chemical diversity with a high level of accuracy. To address this gap, Meta FAIR introduces Open Molecules 2025 (OMol25), a large-scale dataset composed of more than 100 million density functional theory (DFT) calculations at the omegaB97M-V/def2-TZVPD level of theory, representing billions of CPU core-hours of compute. OMol25 uniquely blends elemental, chemical, and structural diversity including: 83 elements, a wide-range of intra- and intermolecular interactions, explicit solvation, variable charge/spin, conformers, and reactive structures. There are ~83M unique molecular systems in OMol25 covering small molecules, biomolecules, metal complexes, and electrolytes, including structures obtained from existing datasets. OMol25 also greatly expands on the size of systems typically included in DFT datasets, with systems of up to 350 atoms. In addition to the public release of the data, we provide baseline models and a comprehensive set of model evaluations to encourage community engagement in developing the next-generation ML models for molecular chemistry.

Molecular Representation Learning (MRL) has proven impactful in numerous biochemical applications such as drug discovery and enzyme design. While Graph Neural Networks (GNNs) are effective at learning molecular representations from a 2D molecular graph or a single 3D structure, existing works often overlook the flexible nature of molecules, which continuously interconvert across conformations via chemical bond rotations and minor vibrational perturbations. To better account for molecular flexibility, some recent works formulate MRL as an ensemble learning problem, focusing on explicitly learning from a set of conformer structures. However, most of these studies have limited datasets, tasks, and models. In this work, we introduce the first MoleculAR Conformer Ensemble Learning (MARCEL) benchmark to thoroughly evaluate the potential of learning on conformer ensembles and suggest promising research directions. MARCEL includes four datasets covering diverse molecule- and reaction-level properties of chemically diverse molecules including organocatalysts and transition-metal catalysts, extending beyond the scope of common GNN benchmarks that are confined to drug-like molecules. In addition, we conduct a comprehensive empirical study, which benchmarks representative 1D, 2D, and 3D molecular representation learning models, along with two strategies that explicitly incorporate conformer ensembles into 3D MRL models. Our findings reveal that direct learning from an accessible conformer space can improve performance on a variety of tasks and models.

Unlocking deep, interpretable biological reasoning from complex genomic data is a major AI challenge hindering scientific discovery. Current DNA foundation models, despite strong sequence representation, struggle with multi-step reasoning and lack inherent transparent, biologically intuitive explanations. We introduce BioReason, a pioneering architecture that, for the first time, deeply integrates a DNA foundation model with a Large Language Model (LLM). This novel connection enables the LLM to directly process and reason with genomic information as a fundamental input, fostering a new form of multimodal biological understanding. BioReason's sophisticated multi-step reasoning is developed through supervised fine-tuning and targeted reinforcement learning, guiding the system to generate logical, biologically coherent deductions. On biological reasoning benchmarks including KEGG-based disease pathway prediction - where accuracy improves from 88% to 97% - and variant effect prediction, BioReason demonstrates an average 15% performance gain over strong single-modality baselines. BioReason reasons over unseen biological entities and articulates decision-making through interpretable, step-by-step biological traces, offering a transformative approach for AI in biology that enables deeper mechanistic insights and accelerates testable hypothesis generation from genomic data. Data, code, and checkpoints are publicly available at https://github.com/bowang-lab/BioReason

Understanding the 3D structures of protein multimers is crucial, as they play a vital role in regulating various cellular processes. It has been empirically confirmed that the multimer structure prediction~(MSP) can be well handled in a step-wise assembly fashion using provided dimer structures and predicted protein-protein interactions~(PPIs). However, due to the biological gap in the formation of dimers and larger multimers, directly applying PPI prediction techniques can often cause a poor generalization to the MSP task. To address this challenge, we aim to extend the PPI knowledge to multimers of different scales~(i.e., chain numbers). Specifically, we propose \textsc{PromptMSP}, a pre-training and Prompt tuning framework for Multimer Structure Prediction. First, we tailor the source and target tasks for effective PPI knowledge learning and efficient inference, respectively. We design PPI-inspired prompt learning to narrow the gaps of two task formats and generalize the PPI knowledge to multimers of different scales. We provide a meta-learning strategy to learn a reliable initialization of the prompt model, enabling our prompting framework to effectively adapt to limited data for large-scale multimers. Empirically, we achieve both significant accuracy (RMSD and TM-Score) and efficiency improvements compared to advanced MSP models. The code, data and checkpoints are released at https://github.com/zqgao22/PromptMSP.

The success of language models, especially transformer-based architectures, has trickled into other domains giving rise to "scientific language models" that operate on small molecules, proteins or polymers. In chemistry, language models contribute to accelerating the molecule discovery cycle as evidenced by promising recent findings in early-stage drug discovery. Here, we review the role of language models in molecular discovery, underlining their strength in de novo drug design, property prediction and reaction chemistry. We highlight valuable open-source software assets thus lowering the entry barrier to the field of scientific language modeling. Last, we sketch a vision for future molecular design that combines a chatbot interface with access to computational chemistry tools. Our contribution serves as a valuable resource for researchers, chemists, and AI enthusiasts interested in understanding how language models can and will be used to accelerate chemical discovery.

Protein representation learning is critical for numerous biological tasks. Recently, large transformer-based protein language models (pLMs) pretrained on large scale protein sequences have demonstrated significant success in sequence-based tasks. However, pLMs lack structural context. Conversely, graph neural networks (GNNs) designed to leverage 3D structural information have shown promising generalization in protein-related prediction tasks, but their effectiveness is often constrained by the scarcity of labeled structural data. Recognizing that sequence and structural representations are complementary perspectives of the same protein entity, we propose a multimodal bidirectional hierarchical fusion framework to effectively merge these modalities. Our framework employs attention and gating mechanisms to enable effective interaction between pLMs-generated sequential representations and GNN-extracted structural features, improving information exchange and enhancement across layers of the neural network. This bidirectional and hierarchical (Bi-Hierarchical) fusion approach leverages the strengths of both modalities to capture richer and more comprehensive protein representations. Based on the framework, we further introduce local Bi-Hierarchical Fusion with gating and global Bi-Hierarchical Fusion with multihead self-attention approaches. Our method demonstrates consistent improvements over strong baselines and existing fusion techniques in a variety of protein representation learning benchmarks, including enzyme EC classification, model quality assessment, protein-ligand binding affinity prediction, protein-protein binding site prediction, and B cell epitopes prediction. Our method establishes a new state-of-the-art for multimodal protein representation learning, emphasizing the efficacy of Bi-Hierarchical Fusion in bridging sequence and structural modalities.

Discovering novel drug candidate molecules is one of the most fundamental and critical steps in drug development. Generative deep learning models, which create synthetic data given a probability distribution, offer a high potential for designing de novo molecules. However, to be utilisable in real life drug development pipelines, these models should be able to design drug like and target centric molecules. In this study, we propose an end to end generative system, DrugGEN, for the de novo design of drug candidate molecules that interact with intended target proteins. The proposed method represents molecules as graphs and processes them via a generative adversarial network comprising graph transformer layers. The system is trained using a large dataset of drug like compounds and target specific bioactive molecules to design effective inhibitory molecules against the AKT1 protein, which is critically important in developing treatments for various types of cancer. We conducted molecular docking and dynamics to assess the target centric generation performance of the model, as well as attention score visualisation to examine model interpretability. In parallel, selected compounds were chemically synthesised and evaluated in the context of in vitro enzymatic assays, which identified two bioactive molecules that inhibited AKT1 at low micromolar concentrations. These results indicate that DrugGEN's de novo molecules have a high potential for interacting with the AKT1 protein at the level of its native ligands. Using the open access DrugGEN codebase, it is possible to easily train models for other druggable proteins, given a dataset of experimentally known bioactive molecules.

Molecular relational learning, whose goal is to learn the interaction behavior between molecular pairs, got a surge of interest in molecular sciences due to its wide range of applications. Recently, graph neural networks have recently shown great success in molecular relational learning by modeling a molecule as a graph structure, and considering atom-level interactions between two molecules. Despite their success, existing molecular relational learning methods tend to overlook the nature of chemistry, i.e., a chemical compound is composed of multiple substructures such as functional groups that cause distinctive chemical reactions. In this work, we propose a novel relational learning framework, called CGIB, that predicts the interaction behavior between a pair of graphs by detecting core subgraphs therein. The main idea is, given a pair of graphs, to find a subgraph from a graph that contains the minimal sufficient information regarding the task at hand conditioned on the paired graph based on the principle of conditional graph information bottleneck. We argue that our proposed method mimics the nature of chemical reactions, i.e., the core substructure of a molecule varies depending on which other molecule it interacts with. Extensive experiments on various tasks with real-world datasets demonstrate the superiority of CGIB over state-of-the-art baselines. Our code is available at https://github.com/Namkyeong/CGIB.

Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm.

There is widespread optimism that frontier Large Language Models (LLMs) and LLM-augmented systems have the potential to rapidly accelerate scientific discovery across disciplines. Today, many benchmarks exist to measure LLM knowledge and reasoning on textbook-style science questions, but few if any benchmarks are designed to evaluate language model performance on practical tasks required for scientific research, such as literature search, protocol planning, and data analysis. As a step toward building such benchmarks, we introduce the Language Agent Biology Benchmark (LAB-Bench), a broad dataset of over 2,400 multiple choice questions for evaluating AI systems on a range of practical biology research capabilities, including recall and reasoning over literature, interpretation of figures, access and navigation of databases, and comprehension and manipulation of DNA and protein sequences. Importantly, in contrast to previous scientific benchmarks, we expect that an AI system that can achieve consistently high scores on the more difficult LAB-Bench tasks would serve as a useful assistant for researchers in areas such as literature search and molecular cloning. As an initial assessment of the emergent scientific task capabilities of frontier language models, we measure performance of several against our benchmark and report results compared to human expert biology researchers. We will continue to update and expand LAB-Bench over time, and expect it to serve as a useful tool in the development of automated research systems going forward. A public subset of LAB-Bench is available for use at the following URL: https://huggingface.co/datasets/futurehouse/lab-bench

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Through evolution, nature has presented a set of remarkable protein materials, including elastins, silks, keratins and collagens with superior mechanical performances that play crucial roles in mechanobiology. However, going beyond natural designs to discover proteins that meet specified mechanical properties remains challenging. Here we report a generative model that predicts protein designs to meet complex nonlinear mechanical property-design objectives. Our model leverages deep knowledge on protein sequences from a pre-trained protein language model and maps mechanical unfolding responses to create novel proteins. Via full-atom molecular simulations for direct validation, we demonstrate that the designed proteins are novel, and fulfill the targeted mechanical properties, including unfolding energy and mechanical strength, as well as the detailed unfolding force-separation curves. Our model offers rapid pathways to explore the enormous mechanobiological protein sequence space unconstrained by biological synthesis, using mechanical features as target to enable the discovery of protein materials with superior mechanical properties.

Recent advancements in specialized large-scale architectures for training image and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT4 have demonstrated exceptional capabilities in processing, translating, and generating human languages. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Language models, in particular, have seen widespread use in protein research, as they have been utilized to embed proteins, generate novel ones, and predict tertiary structures. In this book chapter, we provide an overview of the use of protein generative models, reviewing 1) language models for the design of novel artificial proteins, 2) works that use non-Transformer architectures, and 3) applications in directed evolution approaches.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

Many proteins useful in modern medicine or bioengineering are challenging to make in the lab, fuse with other proteins in cells, or deliver to tissues in the body, because their sequences are too long. Shortening these sequences typically involves costly, time-consuming experimental campaigns. Ideally, we could instead use modern models of massive databases of sequences from nature to learn how to propose shrunken proteins that resemble sequences found in nature. Unfortunately, these models struggle to efficiently search the combinatorial space of all deletions, and are not trained with inductive biases to learn how to delete. To address this gap, we propose SCISOR, a novel discrete diffusion model that deletes letters from sequences to generate protein samples that resemble those found in nature. To do so, SCISOR trains a de-noiser to reverse a forward noising process that adds random insertions to natural sequences. As a generative model, SCISOR fits evolutionary sequence data competitively with previous large models. In evaluation, SCISOR achieves state-of-the-art predictions of the functional effects of deletions on ProteinGym. Finally, we use the SCISOR de-noiser to shrink long protein sequences, and show that its suggested deletions result in significantly more realistic proteins and more often preserve functional motifs than previous models of evolutionary sequences.

The success of drug discovery and development relies on the precise prediction of molecular activities and properties. While in silico molecular property prediction has shown remarkable potential, its use has been limited so far to assays for which large amounts of data are available. In this study, we use a fine-tuned large language model to integrate biological assays based on their textual information, coupled with Barlow Twins, a Siamese neural network using a novel self-supervised learning approach. This architecture uses both assay information and molecular fingerprints to extract the true molecular information. TwinBooster enables the prediction of properties of unseen bioassays and molecules by providing state-of-the-art zero-shot learning tasks. Remarkably, our artificial intelligence pipeline shows excellent performance on the FS-Mol benchmark. This breakthrough demonstrates the application of deep learning to critical property prediction tasks where data is typically scarce. By accelerating the early identification of active molecules in drug discovery and development, this method has the potential to help streamline the identification of novel therapeutics.

A suitable feature representation that can both preserve the data intrinsic information and reduce data complexity and dimensionality is key to the performance of machine learning models. Deeply rooted in algebraic topology, persistent homology (PH) provides a delicate balance between data simplification and intrinsic structure characterization, and has been applied to various areas successfully. However, the combination of PH and machine learning has been hindered greatly by three challenges, namely topological representation of data, PH-based distance measurements or metrics, and PH-based feature representation. With the development of topological data analysis, progresses have been made on all these three problems, but widely scattered in different literatures. In this paper, we provide a systematical review of PH and PH-based supervised and unsupervised models from a computational perspective. Our emphasizes are the recent development of mathematical models and tools, including PH softwares and PH-based functions, feature representations, kernels, and similarity models. Essentially, this paper can work as a roadmap for the practical application of PH-based machine learning tools. Further, we consider different topological feature representations in different machine learning models, and investigate their impacts on the protein secondary structure classification.

Predicting which proteins interact together from amino-acid sequences is an important task. We develop a method to pair interacting protein sequences which leverages the power of protein language models trained on multiple sequence alignments, such as MSA Transformer and the EvoFormer module of AlphaFold. We formulate the problem of pairing interacting partners among the paralogs of two protein families in a differentiable way. We introduce a method called DiffPALM that solves it by exploiting the ability of MSA Transformer to fill in masked amino acids in multiple sequence alignments using the surrounding context. MSA Transformer encodes coevolution between functionally or structurally coupled amino acids. We show that it captures inter-chain coevolution, while it was trained on single-chain data, which means that it can be used out-of-distribution. Relying on MSA Transformer without fine-tuning, DiffPALM outperforms existing coevolution-based pairing methods on difficult benchmarks of shallow multiple sequence alignments extracted from ubiquitous prokaryotic protein datasets. It also outperforms an alternative method based on a state-of-the-art protein language model trained on single sequences. Paired alignments of interacting protein sequences are a crucial ingredient of supervised deep learning methods to predict the three-dimensional structure of protein complexes. DiffPALM substantially improves the structure prediction of some eukaryotic protein complexes by AlphaFold-Multimer, without significantly deteriorating any of those we tested. It also achieves competitive performance with using orthology-based pairing.

Building a working mental model of a protein typically requires weeks of reading, cross-referencing crystal and predicted structures, and inspecting ligand complexes, an effort that is slow, unevenly accessible, and often requires specialized computational skills. We introduce Speak to a Protein, a new capability that turns protein analysis into an interactive, multimodal dialogue with an expert co-scientist. The AI system retrieves and synthesizes relevant literature, structures, and ligand data; grounds answers in a live 3D scene; and can highlight, annotate, manipulate and see the visualization. It also generates and runs code when needed, explaining results in both text and graphics. We demonstrate these capabilities on relevant proteins, posing questions about binding pockets, conformational changes, or structure-activity relationships to test ideas in real-time. Speak to a Protein reduces the time from question to evidence, lowers the barrier to advanced structural analysis, and enables hypothesis generation by tightly coupling language, code, and 3D structures. Speak to a Protein is freely accessible at https://open.playmolecule.org.

The genome sequence contains the blueprint for governing cellular processes. While the availability of genomes has vastly increased over the last decades, experimental annotation of the various functional, non-coding and regulatory elements encoded in the DNA sequence remains both expensive and challenging. This has sparked interest in unsupervised language modeling of genomic DNA, a paradigm that has seen great success for protein sequence data. Although various DNA language models have been proposed, evaluation tasks often differ between individual works, and might not fully recapitulate the fundamental challenges of genome annotation, including the length, scale and sparsity of the data. In this study, we introduce BEND, a Benchmark for DNA language models, featuring a collection of realistic and biologically meaningful downstream tasks defined on the human genome. We find that embeddings from current DNA LMs can approach performance of expert methods on some tasks, but only capture limited information about long-range features. BEND is available at https://github.com/frederikkemarin/BEND.

Numerous biological and physical processes can be modeled as systems of interacting entities evolving continuously over time, e.g. the dynamics of communicating cells or physical particles. Learning the dynamics of such systems is essential for predicting the temporal evolution of populations across novel samples and unseen environments. Flow-based models allow for learning these dynamics at the population level - they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We argue that multiple processes in natural sciences have to be represented as vector fields on the Wasserstein manifold of probability densities. That is, the change of the population at any moment in time depends on the population itself due to the interactions between samples. In particular, this is crucial for personalized medicine where the development of diseases and their respective treatment response depends on the microenvironment of cells specific to each patient. We propose Meta Flow Matching (MFM), a practical approach to integrating along these vector fields on the Wasserstein manifold by amortizing the flow model over the initial populations. Namely, we embed the population of samples using a Graph Neural Network (GNN) and use these embeddings to train a Flow Matching model. This gives MFM the ability to generalize over the initial distributions unlike previously proposed methods. We demonstrate the ability of MFM to improve prediction of individual treatment responses on a large scale multi-patient single-cell drug screen dataset.

Molecular dynamics (MD) simulation is a widely used technique to simulate molecular systems, most commonly at the all-atom resolution where equations of motion are integrated with timesteps on the order of femtoseconds (1fs=10^{-15}s). MD is often used to compute equilibrium properties, which requires sampling from an equilibrium distribution such as the Boltzmann distribution. However, many important processes, such as binding and folding, occur over timescales of milliseconds or beyond, and cannot be efficiently sampled with conventional MD. Furthermore, new MD simulations need to be performed for each molecular system studied. We present Timewarp, an enhanced sampling method which uses a normalising flow as a proposal distribution in a Markov chain Monte Carlo method targeting the Boltzmann distribution. The flow is trained offline on MD trajectories and learns to make large steps in time, simulating the molecular dynamics of 10^{5} - 10^{6}:fs. Crucially, Timewarp is transferable between molecular systems: once trained, we show that it generalises to unseen small peptides (2-4 amino acids) at all-atom resolution, exploring their metastable states and providing wall-clock acceleration of sampling compared to standard MD. Our method constitutes an important step towards general, transferable algorithms for accelerating MD.

Accumulated clinical studies show that microbes living in humans interact closely with human hosts, and get involved in modulating drug efficacy and drug toxicity. Microbes have become novel targets for the development of antibacterial agents. Therefore, screening of microbe-drug associations can benefit greatly drug research and development. With the increase of microbial genomic and pharmacological datasets, we are greatly motivated to develop an effective computational method to identify new microbe-drug associations. In this paper, we proposed a novel method, Graph2MDA, to predict microbe-drug associations by using variational graph autoencoder (VGAE). We constructed multi-modal attributed graphs based on multiple features of microbes and drugs, such as molecular structures, microbe genetic sequences, and function annotations. Taking as input the multi-modal attribute graphs, VGAE was trained to learn the informative and interpretable latent representations of each node and the whole graph, and then a deep neural network classifier was used to predict microbe-drug associations. The hyperparameter analysis and model ablation studies showed the sensitivity and robustness of our model. We evaluated our method on three independent datasets and the experimental results showed that our proposed method outperformed six existing state-of-the-art methods. We also explored the meaningness of the learned latent representations of drugs and found that the drugs show obvious clustering patterns that are significantly consistent with drug ATC classification. Moreover, we conducted case studies on two microbes and two drugs and found 75\%-95\% predicted associations have been reported in PubMed literature. Our extensive performance evaluations validated the effectiveness of our proposed method.\

The transcriptional response to genetic perturbation reveals fundamental insights into complex cellular systems. While current approaches have made progress in predicting genetic perturbation responses, they provide limited biological understanding and cannot systematically refine existing knowledge. Overcoming these limitations requires an end-to-end integration of data-driven learning and existing knowledge. However, this integration is challenging due to inconsistencies between data and knowledge bases, such as noise, misannotation, and incompleteness. To address this challenge, we propose ALIGNED (Adaptive aLignment for Inconsistent Genetic kNowledgE and Data), a neuro-symbolic framework based on the Abductive Learning (ABL) paradigm. This end-to-end framework aligns neural and symbolic components and performs systematic knowledge refinement. We introduce a balanced consistency metric to evaluate the predictions' consistency against both data and knowledge. Our results show that ALIGNED outperforms state-of-the-art methods by achieving the highest balanced consistency, while also re-discovering biologically meaningful knowledge. Our work advances beyond existing methods to enable both the transparency and the evolution of mechanistic biological understanding.

Molecule pretraining has quickly become the go-to schema to boost the performance of AI-based drug discovery. Naturally, molecules can be represented as 2D topological graphs or 3D geometric point clouds. Although most existing pertaining methods focus on merely the single modality, recent research has shown that maximizing the mutual information (MI) between such two modalities enhances the molecule representation ability. Meanwhile, existing molecule multi-modal pretraining approaches approximate MI based on the representation space encoded from the topology and geometry, thus resulting in the loss of critical structural information of molecules. To address this issue, we propose MoleculeSDE. MoleculeSDE leverages group symmetric (e.g., SE(3)-equivariant and reflection-antisymmetric) stochastic differential equation models to generate the 3D geometries from 2D topologies, and vice versa, directly in the input space. It not only obtains tighter MI bound but also enables prosperous downstream tasks than the previous work. By comparing with 17 pretraining baselines, we empirically verify that MoleculeSDE can learn an expressive representation with state-of-the-art performance on 26 out of 32 downstream tasks.

The discovery of novel materials and functional molecules can help to solve some of society's most urgent challenges, ranging from efficient energy harvesting and storage to uncovering novel pharmaceutical drug candidates. Traditionally matter engineering -- generally denoted as inverse design -- was based massively on human intuition and high-throughput virtual screening. The last few years have seen the emergence of significant interest in computer-inspired designs based on evolutionary or deep learning methods. The major challenge here is that the standard strings molecular representation SMILES shows substantial weaknesses in that task because large fractions of strings do not correspond to valid molecules. Here, we solve this problem at a fundamental level and introduce SELFIES (SELF-referencIng Embedded Strings), a string-based representation of molecules which is 100\% robust. Every SELFIES string corresponds to a valid molecule, and SELFIES can represent every molecule. SELFIES can be directly applied in arbitrary machine learning models without the adaptation of the models; each of the generated molecule candidates is valid. In our experiments, the model's internal memory stores two orders of magnitude more diverse molecules than a similar test with SMILES. Furthermore, as all molecules are valid, it allows for explanation and interpretation of the internal working of the generative models.

Language-molecule models have emerged as an exciting direction for molecular discovery and understanding. However, training these models is challenging due to the scarcity of molecule-language pair datasets. At this point, datasets have been released which are 1) small and scraped from existing databases, 2) large but noisy and constructed by performing entity linking on the scientific literature, and 3) built by converting property prediction datasets to natural language using templates. In this document, we detail the L+M-24 dataset, which has been created for the Language + Molecules Workshop shared task at ACL 2024. In particular, L+M-24 is designed to focus on three key benefits of natural language in molecule design: compositionality, functionality, and abstraction.

Predicting drug efficacy and safety in vivo requires information on biological responses (e.g., cell morphology and gene expression) to small molecule perturbations. However, current molecular representation learning methods do not provide a comprehensive view of cell states under these perturbations and struggle to remove noise, hindering model generalization. We introduce the Information Alignment (InfoAlign) approach to learn molecular representations through the information bottleneck method in cells. We integrate molecules and cellular response data as nodes into a context graph, connecting them with weighted edges based on chemical, biological, and computational criteria. For each molecule in a training batch, InfoAlign optimizes the encoder's latent representation with a minimality objective to discard redundant structural information. A sufficiency objective decodes the representation to align with different feature spaces from the molecule's neighborhood in the context graph. We demonstrate that the proposed sufficiency objective for alignment is tighter than existing encoder-based contrastive methods. Empirically, we validate representations from InfoAlign in two downstream tasks: molecular property prediction against up to 19 baseline methods across four datasets, plus zero-shot molecule-morphology matching.

Complex chemical structures, like drugs, are usually defined by SMILES strings as a sequence of molecules and bonds. These SMILES strings are used in different complex machine learning-based drug-related research and representation works. Escaping from complex representation, in this work, we pose a single question: What if we treat drug SMILES as conventional sentences and engage in text classification for drug classification? Our experiments affirm the possibility with very competitive scores. The study explores the notion of viewing each atom and bond as sentence components, employing basic NLP methods to categorize drug types, proving that complex problems can also be solved with simpler perspectives. The data and code are available here: https://github.com/azminewasi/Drug-Classification-NLP.