Deep Learning Model for Amyloidogenicity Prediction using a Pre-trained Protein LLM

Abstract: The prediction of amyloidogenicity in peptides and proteins remains a focal point of ongoing bioinformatics. The crucial step in this field is to apply advanced computational methodologies. Many recent approaches to predicting amyloidogenicity within proteins are highly based on evolutionary motifs and the individual properties of amino acids. It is becoming increasingly evident that the sequence information-based features show high predictive performance. Consequently, our study evaluated the contextual features of protein sequences obtained from a pretrained protein large language model leveraging bidirectional LSTM and GRU to predict amyloidogenic regions in peptide and protein sequences. Our method achieved an accuracy of 84.5% on 10-fold cross-validation and an accuracy of 83% in the test dataset. Our results demonstrate competitive performance, highlighting the potential of LLMs in enhancing the accuracy of amyloid prediction.


Driving Accurate Allergen Prediction with Protein Language Models and Generalization-Focused Evaluation

Abstract: Allergens, typically proteins capable of triggering adverse immune responses, represent a significant public health challenge. To accurately identify allergen proteins, we introduce Applm (Allergen Prediction with Protein Language Models), a computational framework that leverages the 100-billion parameter xTrimoPGLM protein language model. We show that Applm consistently outperforms seven state-of-the-art methods in a diverse set of tasks that closely resemble difficult real-world scenarios. These include identifying novel allergens that lack similar examples in the training set, differentiating between allergens and non-allergens among homologs with high sequence similarity, and assessing functional consequences of mutations that create few changes to the protein sequences. Our analysis confirms that xTrimoPGLM, originally trained on one trillion tokens to capture general protein sequence characteristics, is crucial for Applm's performance by detecting important differences among protein sequences. In addition to providing Applm as open-source software, we also provide our carefully curated benchmark datasets to facilitate future research.

Brian Shing-Hei Wong
Joshua Mincheol Kim
Sin-Hang Fung
Qing Xiong
Kelvin Fu-Kiu Ao
Junkang Wei
Ran Wang
Dan Michelle Wang
Jingying Zhou
Bo Feng
Alfred Sze-Lok Cheng
Kevin Y. Yip
Stephen Kwok-Wing Tsui
Qin Cao


Energy-Based Models for Predicting Mutational Effects on Proteins

Abstract: Predicting changes in binding free energy ($ΔΔG$) is a vital task in protein engineering and protein-protein interaction (PPI) engineering for drug discovery. Previous works have observed a high correlation between $ΔΔG$ and entropy, using probabilities of biologically important objects such as side chain angles and residue identities to estimate $ΔΔG$. However, estimating the full conformational distribution of a protein complex is generally considered intractable. In this work, we propose a new approach to $ΔΔG$ prediction that avoids this issue by instead leveraging energy-based models for estimating the probability of a complex's conformation. Specifically, we novelly decompose $ΔΔG$ into a sequence-based component estimated by an inverse folding model and a structure-based component estimated by an energy model. This decomposition is made tractable by assuming equilibrium between the bound and unbound states, allowing us to simplify the estimation of degeneracies associated with each state. Unlike previous deep learning-based methods, our method incorporates an energy-based physical inductive bias by connecting the often-used sequence log-odds ratio-based approach to $ΔΔG$ prediction with a new $ΔΔE$ term grounded in statistical mechanics. We demonstrate superiority over existing state-of-the-art structure and sequence-based deep learning methods in $ΔΔG$ prediction and antibody optimization against SARS-CoV-2.

Patrick Soga
Zhenyu Lei
Yinhan He
Camille Bilodeau
Jundong Li


Not Yet AlphaFold for the Mind: Evaluating Centaur as a Synthetic Participant

Abstract: Simulators have revolutionized scientific practice across the natural sciences. By generating data that reliably approximate real-world phenomena, they enable scientists to accelerate hypothesis testing and optimize experimental designs. This is perhaps best illustrated by AlphaFold, a Nobel-prize winning simulator in chemistry that predicts protein structures from amino acid sequences, enabling rapid prototyping of molecular interactions, drug targets, and protein functions. In the behavioral sciences, a reliable participant simulator - a system capable of producing human-like behavior across cognitive tasks - would represent a similarly transformative advance. Recently, Binz et al. introduced Centaur, a large language model (LLM) fine-tuned on human data from 160 experiments, proposing its use not only as a model of cognition but also as a participant simulator for "in silico prototyping of experimental studies", e.g., to advance automated cognitive science. Here, we review the core criteria for a participant simulator and assess how well Centaur meets them. Although Centaur demonstrates strong predictive accuracy, its generative behavior - a critical criterion for a participant simulator - systematically diverges from human data. This suggests that, while Centaur is a significant step toward predicting human behavior, it does not yet meet the standards of a reliable participant simulator or an accurate model of cognition.

Sabrina Namazova
Alessandra Brondetta
Younes Strittmatter
Matthew Nassar
Sebastian Musslick


Scaling and Data Saturation in Protein Language Models

Abstract: Data in biology is redundant, noisy, and sparse. How does the type and scale of available data impact model performance? In this work, we specifically investigate how protein language models (pLMs) scale with increasing pretraining data. We investigate this relationship by measuring the performance of protein function prediction on a suite of pLMs pretrained on yearly snapshots of UniRef100 from 2011 to 2024. We find no evidence of model saturation on this task: performance improves--but not monotonically--with added data, and this trend differs between unsupervised and supervised experiments. Using a well-characterized Beta-Lactamase protein from E. coli, we find that unsupervised model predictions get better year-over-year, though they do not yet consistently perform better than the supervised baseline. Our results underscore the need for targeted data acquisition and deeper study of data scaling in protein modeling. All training, inference, analysis, and visualization code is available at: https://github.com/Align-to-Innovate/data-saturation-and-scaling.

Aviv Spinner
Erika DeBenedictis
Corey M. Hudson


A novel language model for predicting serious adverse event results in clinical trials from their prospective registrations

Abstract: Objectives: With accurate estimates of expected safety results, clinical trials could be better designed and monitored. We evaluated methods for predicting serious adverse event (SAE) results in clinical trials using information only from their registrations prior to the trial. Material and Methods: We analyzed 22,107 two-arm parallel interventional clinical trials from ClinicalTrials.gov with structured summary results. Two prediction models were developed: a classifier predicting whether a greater proportion of participants in an experimental arm would have SAEs (area under the receiver operating characteristic curve; AUC) compared to the control arm, and a regression model to predict the proportion of participants with SAEs in the control arms (root mean squared error; RMSE). A transfer learning approach using pretrained language models (e.g., ClinicalT5, BioBERT) was used for feature extraction, combined with a downstream model for prediction. To maintain semantic representation in long trial texts exceeding localized language model input limits, a sliding window method was developed for embedding extraction. Results: The best model (ClinicalT5+Transformer+MLP) had 77.6% AUC when predicting which trial arm had a higher proportion of SAEs. When predicting SAE proportion in the control arm, the same model achieved RMSE of 18.6%. The sliding window approach consistently outperformed direct comparisons. Across 12 classifiers, the average absolute AUC increase was 2.00%, and absolute RMSE reduction was 1.58% across 12 regressors. Discussion: Summary results data from ClinicalTrials.gov remains underutilized. Predicted results of publicly reported trials provides an opportunity to identify discrepancies between expected and reported safety results.

Qixuan Hu
Xumou Zhang
Jinman Kim
Florence Bourgeois
Adam G. Dunn


Continued domain-specific pre-training of protein language models for pMHC-I binding prediction

Abstract: Predicting peptide--major histocompatibility complex I (pMHC-I) binding affinity remains challenging due to extreme allelic diversity ($\sim$30,000 HLA alleles), severe data scarcity for most alleles, and noisy experimental measurements. Current methods particularly struggle with underrepresented alleles and quantitative binding prediction. We test whether domain-specific continued pre-training of protein language models is beneficial for their application to pMHC-I binding affinity prediction. Starting from ESM Cambrian (300M parameters), we perform masked-language modeling (MLM)-based continued pre-training on HLA-associated peptides (epitopes), testing two input formats: epitope sequences alone versus epitopes concatenated with HLA heavy chain sequences. We then fine-tune for functional IC$_{50}$ binding affinity prediction using only high-quality quantitative data, avoiding mass spectrometry biases that are inherited by existing methods.

Sergio E. Mares
Ariel Espinoza Weinberger
Nilah M. Ioannidis


Conformation-Aware Structure Prediction of Antigen-Recognizing Immune Proteins

Abstract: We introduce Ibex, a pan-immunoglobulin structure prediction model that achieves state-of-the-art accuracy in modeling the variable domains of antibodies, nanobodies, and T-cell receptors. Unlike previous approaches, Ibex explicitly distinguishes between bound and unbound protein conformations by training on labeled apo and holo structural pairs, enabling accurate prediction of both states at inference time. Using a comprehensive private dataset of high-resolution antibody structures, we demonstrate superior out-of-distribution performance compared to existing specialized and general protein structure prediction tools. Ibex combines the accuracy of cutting-edge models with significantly reduced computational requirements, providing a robust foundation for accelerating large molecule design and therapeutic development.

Frédéric A. Dreyer
Jan Ludwiczak
Karolis Martinkus
Brennan Abanades
Robert G. Alberstein
Pan Kessel
Pranav Rao
Jae Hyeon Lee
Richard Bonneau
Andrew M. Watkins
Franziska Seeger


PRING: Rethinking Protein-Protein Interaction Prediction from Pairs to Graphs

Abstract: Deep learning-based computational methods have achieved promising results in predicting protein-protein interactions (PPIs). However, existing benchmarks predominantly focus on isolated pairwise evaluations, overlooking a model's capability to reconstruct biologically meaningful PPI networks, which is crucial for biology research. To address this gap, we introduce PRING, the first comprehensive benchmark that evaluates protein-protein interaction prediction from a graph-level perspective. PRING curates a high-quality, multi-species PPI network dataset comprising 21,484 proteins and 186,818 interactions, with well-designed strategies to address both data redundancy and leakage. Building on this golden-standard dataset, we establish two complementary evaluation paradigms: (1) topology-oriented tasks, which assess intra and cross-species PPI network construction, and (2) function-oriented tasks, including protein complex pathway prediction, GO module analysis, and essential protein justification. These evaluations not only reflect the model's capability to understand the network topology but also facilitate protein function annotation, biological module detection, and even disease mechanism analysis. Extensive experiments on four representative model categories, consisting of sequence similarity-based, naive sequence-based, protein language model-based, and structure-based approaches, demonstrate that current PPI models have potential limitations in recovering both structural and functional properties of PPI networks, highlighting the gap in supporting real-world biological applications. We believe PRING provides a reliable platform to guide the development of more effective PPI prediction models for the community. The dataset and source code of PRING are available at https://github.com/SophieSarceau/PRING.

Xinzhe Zheng
Hao Du
Fanding Xu
Jinzhe Li
Zhiyuan Liu
Wenkang Wang
Tao Chen
Wanli Ouyang
Stan Z. Li
Yan Lu
Nanqing Dong
Yang Zhang


ElliottAgents: A Natural Language-Driven Multi-Agent System for Stock Market Analysis and Prediction

Abstract: This paper presents ElliottAgents, a multi-agent system leveraging natural language processing (NLP) and large language models (LLMs) to analyze complex stock market data. The system combines AI-driven analysis with the Elliott Wave Principle to generate human-comprehensible predictions and explanations. A key feature is the natural language dialogue between agents, enabling collaborative analysis refinement. The LLM-enhanced architecture facilitates advanced language understanding, reasoning, and autonomous decision-making. Experiments demonstrate the system's effectiveness in pattern recognition and generating natural language descriptions of market trends. ElliottAgents contributes to NLP applications in specialized domains, showcasing how AI-driven dialogue systems can enhance collaborative analysis in data-intensive fields. This research bridges the gap between complex financial data and human understanding, addressing the need for interpretable and adaptive prediction systems in finance.

Pacific Asia Conference on Language, Information and Computation


DeSTA2.5-Audio: Toward General-Purpose Large Audio Language Model with Self-Generated Cross-Modal Alignment

Abstract: We introduce DeSTA2.5-Audio, a general-purpose Large Audio Language Model (LALM) designed for robust auditory perception and instruction-following. Recent LALMs augment Large Language Models (LLMs) with auditory capabilities by training on large-scale audio-instruction datasets. However, existing LALMs have often suffered from the catastrophic forgetting of the LLM's original abilities. Therefore, balancing knowledge retention and audio perception has become a critical challenge. To address this, we revisit the data construction pipeline and propose a self-generated cross-modal alignment strategy in which the backbone LLM generates its own training targets, named DeSTA. This approach aims at preserving the LLM's native language proficiency thereby enabling zero-shot generalization without task-specific tuning. We construct DeSTA-AQA5M, a large-scale, task-agnostic dataset containing 5 million training samples derived from 7,000 hours of audio spanning 50 diverse datasets, including speech, environmental sounds, and music. DeSTA2.5-Audio achieves state-of-the-art or competitive performance across a wide range of audio-language benchmarks, including Dynamic-SUPERB, MMAU, SAKURA, Speech-IFEval, and VoiceBench. Comprehensive comparative studies demonstrate that our self-generated strategy outperforms existing training strategies. Our findings underscore the importance of carefully designed data construction in LALM development and offer practical insights for building robust, general-purpose LALMs.

Ke-Han Lu
Zhehuai Chen
Szu-Wei Fu
Chao-Han Huck Yang
Sung-Feng Huang
Chih-Kai Yang
Chee-En Yu
Chun-Wei Chen
Wei-Chih Chen
Chien-yu Huang
Yi-Cheng Lin
Yu-Xiang Lin
Chi-An Fu
Chun-Yi Kuan
Wenze Ren
Xuanjun Chen
Wei-Ping Huang
En-Pei Hu
Tzu-Quan Lin
Yuan-Kuei Wu
Kuan-Po Huang
Hsiao-Ying Huang
Huang-Cheng Chou
Kai-Wei Chang
Cheng-Han Chiang
Boris Ginsburg
Yu-Chiang Frank Wang
Hung-yi Lee

IEEE Transactions on Audio, Speech, and Language Processing


Steering Protein Language Models

Abstract: Protein Language Models (PLMs), pre-trained on extensive evolutionary data from natural proteins, have emerged as indispensable tools for protein design. While powerful, PLMs often struggle to produce proteins with precisely specified functionalities or properties due to inherent challenges in controlling their outputs. In this work, we investigate the potential of Activation Steering, a technique originally developed for controlling text generation in Large Language Models (LLMs), to direct PLMs toward generating protein sequences with targeted properties. We propose a simple yet effective method that employs activation editing to steer PLM outputs, and extend this approach to protein optimization through a novel editing site identification module. Through comprehensive experiments on lysozyme-like sequence generation and optimization, we demonstrate that our methods can be seamlessly integrated into both auto-encoding and autoregressive PLMs without requiring additional training. These results highlight a promising direction for precise protein engineering using foundation models.

Long-Kai Huang
Rongyi Zhu
Bing He
Jianhua Yao

International Conference on Machine Learning


Self-Organizing Language

Abstract: We introduce a novel paradigm of emergent local memory. It is a continuous-learning completely-parallel content-addressable memory encoding global order. It demonstrates how local constraints on uncoordinated learning can produce topologically protected memories realizing emergent symbolic order. It is therefore a neuro-symbolic bridge. It further has the ability to produce human language without data, by exploiting its own self-organizing dynamics. It teaches us that words arise as a side-effect of emergent symbolic order, and that human language patterns at all structural levels reflect a universal mechanism of word formation (which is subregular). This work answers essential questions about the existence \& origin of all the human language data.


Toward the Explainability of Protein Language Models

Abstract: Protein language models (pLMs) excel in a variety of tasks that range from structure prediction to the design of functional enzymes. However, these models operate as black boxes, and their underlying working principles remain unclear. Here, we survey emerging applications of explainable artificial intelligence (XAI) to pLMs and describe the potential of XAI in protein research. We divide the workflow of protein AI modeling into four information contexts: (i) training sequences, (ii) input prompt, (iii) model architecture, and (iv) input-output pairs. For each, we describe existing methods and applications of XAI. Additionally, from published studies we distil five (potential) roles that XAI can play in protein research: Evaluator, Multitasker, Engineer, Coach, and Teacher, with the Evaluator role being the only one widely adopted so far. These roles aim to help both protein scientists and model developers understand the possibilities and limitations of implementing XAI for predictive and generative tasks. While our analysis focuses on pLMs, both this categorization and roles are broadly applicable to any other model architectures. We conclude by highlighting critical areas of application for the future, including risks related to security, trustworthiness, and bias, and we call for community benchmarks, open-source tooling, domain-specific visualizations, and wet-lab characterization to advance the interpretability of protein AI.


From Data to Knowledge: Evaluating How Efficiently Language Models Learn Facts

Abstract: Sample efficiency is a crucial property of language models with practical implications for training efficiency. In real-world text, information follows a long-tailed distribution. Yet, we expect models to learn and recall frequent and infrequent facts. Sample-efficient models are better equipped to handle this challenge of learning and retaining rare information without requiring excessive exposure. This study analyzes multiple models of varying architectures and sizes, all trained on the same pre-training data. By annotating relational facts with their frequencies in the training corpus, we examine how model performance varies with fact frequency. Our findings show that most models perform similarly on high-frequency facts but differ notably on low-frequency facts. This analysis provides new insights into the relationship between model architecture, size, and factual learning efficiency.

Daniel Christoph
Max Ploner
Patrick Haller
Alan Akbik


PL-Guard: Benchmarking Language Model Safety for Polish

Abstract: Despite increasing efforts to ensure the safety of large language models (LLMs), most existing safety assessments and moderation tools remain heavily biased toward English and other high-resource languages, leaving majority of global languages underexamined. To address this gap, we introduce a manually annotated benchmark dataset for language model safety classification in Polish. We also create adversarially perturbed variants of these samples designed to challenge model robustness. We conduct a series of experiments to evaluate LLM-based and classifier-based models of varying sizes and architectures. Specifically, we fine-tune three models: Llama-Guard-3-8B, a HerBERT-based classifier (a Polish BERT derivative), and PLLuM, a Polish-adapted Llama-8B model. We train these models using different combinations of annotated data and evaluate their performance, comparing it against publicly available guard models. Results demonstrate that the HerBERT-based classifier achieves the highest overall performance, particularly under adversarial conditions.

Aleksandra Krasnodębska
Karolina Seweryn
Szymon Łukasik
Wojciech Kusa


Can structural correspondences ground real world representational content in Large Language Models?

Abstract: Large Language Models (LLMs) such as GPT-4 produce compelling responses to a wide range of prompts. But their representational capacities are uncertain. Many LLMs have no direct contact with extra-linguistic reality: their inputs, outputs and training data consist solely of text, raising the questions (1) can LLMs represent anything and (2) if so, what? In this paper, I explore what it would take to answer these questions according to a structural-correspondence based account of representation, and make an initial survey of this evidence. I argue that the mere existence of structural correspondences between LLMs and worldly entities is insufficient to ground representation of those entities. However, if these structural correspondences play an appropriate role - they are exploited in a way that explains successful task performance - then they could ground real world contents. This requires overcoming a challenge: the text-boundedness of LLMs appears, on the face of it, to prevent them engaging in the right sorts of tasks.


DISPROTBENCH: Uncovering the Functional Limits of Protein Structure Prediction Models in Intrinsically Disordered Regions

Abstract: Intrinsically disordered regions (IDRs) play central roles in cellular function, yet remain poorly evaluated by existing protein structure prediction benchmarks. Current evaluations largely focus on well-folded domains, overlooking three fundamental challenges in realistic biological settings: the structural complexity of proteins, the resulting low availability of reliable ground truth, and prediction uncertainty that can propagate into high-risk downstream failures, such as in drug discovery, protein-protein interaction modeling, and functional annotation. We present DisProtBench, an IDR-centric benchmark that explicitly incorporates prediction uncertainty into the evaluation of protein structure prediction models (PSPMs). To address structural complexity and ground-truth scarcity, we curate and unify a large-scale, multi-modal dataset spanning disease-relevant IDRs, GPCR-ligand interactions, and multimeric protein complexes. To assess predictive uncertainty, we introduce Functional Uncertainty Sensitivity (FUS), a novel prediction uncertainty-stratified metric that quantifies downstream task performance under prediction uncertainty. Using this benchmark, we conduct a systematic evaluation of state-of-the-art PSPMs and reveal clear, task-dependent failure modes. Protein-protein interaction prediction degrades sharply in IDRs, while structure-based drug discovery remains comparatively robust. These effects are largely invisible to standard global accuracy metrics, which overestimate functional reliability under prediction uncertainty. We have open-sourced our benchmark and the codebase at https://github.com/Susan571/DisProtBench.

Xinyue Zeng
Tuo Wang
Adithya Kulkarni
Alexander Lu
Alexandra Ni
Phoebe Xing
Junhan Zhao
Siwei Chen
Dawei Zhou


InstructPro: Natural Language Guided Ligand-Binding Protein Design

Abstract: The de novo design of ligand-binding proteins with tailored functions is essential for advancing biotechnology and molecular medicine, yet existing AI approaches are limited by scarce protein-ligand complex data. To circumvent this data bottleneck, we leverage the abundant natural language descriptions characterizing protein-ligand interactions. Here, we introduce InstructPro, a family of generative models that design proteins following the guidance of natural language instructions and ligand formulas. InstructPro produces protein sequences consistent with specified function descriptions and ligand targets. To enable training and evaluation, we develop InstructProBench, a large-scale dataset of 9.6 million (function description, ligand, protein) triples. We train two model variants -- InstructPro-1B and InstructPro-3B -- that substantially outperform strong baselines. InstructPro-1B achieves an AlphaFold3 ipTM of 0.918 and a binding affinity of -8.764 on seen ligands, while maintaining robust performance in a zero-shot setting with scores of 0.869 and -6.713, respectively. These results are accompanied by novelty scores of 70.1% and 68.8%, underscoring the model's ability to generalize beyond the training set. Furthermore, the model yields a superior binding free energy of -20.9 kcal/mol and an average of 5.82 intermolecular hydrogen bonds, validating its proficiency in designing high-affinity ligand-binding proteins. Notably, scaling to InstructPro-3B further improves the zero-shot ipTM to 0.882, binding affinity to -6.797, and binding free energy to -25.8 kcal/mol, demonstrating clear performance gains associated with increased model capacity. These findings highlight the power of natural language-guided generative models to mitigate the data bottlenecks in traditional structure-based methods, significantly broadening the scope of de novo protein design.

Zhenqiao Song
Ramith Hettiarachchi
Chuan Li
Jianwen Xie
Lei Li


BioLangFusion: Multimodal Fusion of DNA, mRNA, and Protein Language Models

Abstract: We present BioLangFusion, a simple approach for integrating pre-trained DNA, mRNA, and protein language models into unified molecular representations. Motivated by the central dogma of molecular biology (information flow from gene to transcript to protein), we align per-modality embeddings at the biologically meaningful codon level (three nucleotides encoding one amino acid) to ensure direct cross-modal correspondence. BioLangFusion studies three standard fusion techniques: (i) codon-level embedding concatenation, (ii) entropy-regularized attention pooling inspired by multiple-instance learning, and (iii) cross-modal multi-head attention -- each technique providing a different inductive bias for combining modality-specific signals. These methods require no additional pre-training or modification of the base models, allowing straightforward integration with existing sequence-based foundation models. Across five molecular property prediction tasks, BioLangFusion outperforms strong unimodal baselines, showing that even simple fusion of pre-trained models can capture complementary multi-omic information with minimal overhead.

Amina Mollaysa
Artem Moskale
Pushpak Pati
Tommaso Mansi
Mangal Prakash
Rui Liao


AlphaFold Database Debiasing for Robust Inverse Folding

Abstract: The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry, such as inverse folding, exposes a critical limitation. Comparative analysis of structural feature distributions reveals that AFDB structures exhibit distinct statistical regularities, reflecting a systematic geometric bias that deviates from the conformational diversity found in experimentally determined structures from the Protein Data Bank (PDB). While AFDB structures are cleaner and more idealized, PDB structures capture the intrinsic variability and physical realism essential for generalization in downstream tasks. To address this discrepancy, we introduce a Debiasing Structure AutoEncoder (DeSAE) that learns to reconstruct native-like conformations from intentionally corrupted backbone geometries. By training the model to recover plausible structural states, DeSAE implicitly captures a more robust and natural structural manifold. At inference, applying DeSAE to AFDB structures produces debiased structures that significantly improve inverse folding performance across multiple benchmarks. This work highlights the critical impact of subtle systematic biases in predicted structures and presents a principled framework for debiasing, significantly boosting the performance of structure-based learning tasks like inverse folding.

Cheng Tan
Zhenxiao Cao
Zhangyang Gao
Siyuan Li
Yufei Huang
Stan Z. Li


Into the Unknown: From Structure to Disorder in Protein Function Prediction

Abstract: Intrinsically disordered regions (IDRs) account for one-third of the human proteome and play essential biological roles. However, predicting the functions of IDRs remains a major challenge due to their lack of stable structures, rapid sequence evolution, and context-dependent behavior. Many predictors of protein function neglect or underperform on IDRs. Recent advances in computational biology and machine learning, including protein language models, alignment-free approaches, and IDR-specific methods, have revealed conserved bulk features and local motifs within IDRs that are linked to function. This review highlights emerging computational methods that map the sequence-function relationship in IDRs, outlines critical challenges in IDR function annotation, and proposes a community-driven framework to accelerate interpretable functional predictions for IDRs.

Đesika Kolarić
Chi Fung Willis Chow
Rita Zi Zhu
Agnes Toth-Petroczy
T. Reid Alderson
Iva Pritišanac


Multiscale guidance of protein structure prediction with heterogeneous cryo-EM data

Abstract: Protein structure prediction models are now capable of generating accurate 3D structural hypotheses from sequence alone. However, they routinely fail to capture the conformational diversity of dynamic biomolecular complexes, often requiring heuristic MSA subsampling approaches for generating alternative states. In parallel, cryo-electron microscopy (cryo-EM) has emerged as a powerful tool for imaging near-native structural heterogeneity, but is challenged by arduous pipelines to transform raw experimental data into atomic models. Here, we bridge the gap between these modalities, combining cryo-EM density maps with the rich sequence and biophysical priors learned by protein structure prediction models. Our method, CryoBoltz, guides the sampling trajectory of a pretrained biomolecular structure prediction model using both global and local structural constraints derived from density maps, driving predictions towards conformational states consistent with the experimental data. We demonstrate that this flexible yet powerful inference-time approach allows us to build atomic models into heterogeneous cryo-EM maps across a variety of dynamic biomolecular systems including transporters and antibodies. Code is available at https://github.com/ml-struct-bio/cryoboltz .

Rishwanth Raghu
Axel Levy
Gordon Wetzstein
Ellen D. Zhong


Trajectory Prediction Meets Large Language Models: A Survey

Abstract: Recent advances in large language models (LLMs) have sparked growing interest in integrating language-driven techniques into trajectory prediction. By leveraging their semantic and reasoning capabilities, LLMs are reshaping how autonomous systems perceive, model, and predict trajectories. This survey provides a comprehensive overview of this emerging field, categorizing recent work into five directions: (1) Trajectory prediction via language modeling paradigms, (2) Direct trajectory prediction with pretrained language models, (3) Language-guided scene understanding for trajectory prediction, (4) Language-driven data generation for trajectory prediction, (5) Language-based reasoning and interpretability for trajectory prediction. For each, we analyze representative methods, highlight core design choices, and identify open challenges. This survey bridges natural language processing and trajectory prediction, offering a unified perspective on how language can enrich trajectory prediction.

Yi Xu
Ruining Yang
Yitian Zhang
Jianglin Lu
Mingyuan Zhang
Yizhou Wang
Lili Su
Yun Fu


Protein Language Model Zero-Shot Fitness Predictions are Improved by Inference-only Dropout

Abstract: Protein Language Models (PLMs) such as ESM2 have been shown to be capable of zero-shot prediction of critical scalar properties of proteins (fitness). In this work, we show that injecting a dropout layer at inference time between a PLM's featurizer/embedding layer and its transformer, and averaging its output akin to Monte-Carlo dropout increases zero-shot performance on a subset of the ProteinGym dataset. This is the case even when the model was not trained with dropouts to begin with, and does not require retraining or finetuning of the PLM. A dropout of 0.1 seems performant across all models.


Aligning Proteins and Language: A Foundation Model for Protein Retrieval

Abstract: This paper aims to retrieve proteins with similar structures and semantics from large-scale protein dataset, facilitating the functional interpretation of protein structures derived by structural determination methods like cryo-Electron Microscopy (cryo-EM). Motivated by the recent progress of vision-language models (VLMs), we propose a CLIP-style framework for aligning 3D protein structures with functional annotations using contrastive learning. For model training, we propose a large-scale dataset of approximately 200,000 protein-caption pairs with rich functional descriptors. We evaluate our model in both in-domain and more challenging cross-database retrieval on Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB) dataset, respectively. In both cases, our approach demonstrates promising zero-shot retrieval performance, highlighting the potential of multimodal foundation models for structure-function understanding in protein biology.

Qifeng Wu
Zhengzhe Liu
Han Zhu
Yizhou Zhao
Daisuke Kihara
Min Xu


AlphaFold's Bayesian Roots in Probability Kinematics

Abstract: The seminal breakthrough of AlphaFold in protein structure prediction relied on a learned potential energy function parameterized by deep models, in contrast to its successors AlphaFold2 and AlphaFold3, which lack an explicit probabilistic interpretation. While AlphaFold's potential was originally justified by heuristic analogy to physical potentials of mean force, we show that it can instead be understood as a principled instance of probability kinematics (PK), also known as Jeffrey conditioning, a generalization of Bayesian updating. This reinterpretation reveals that AlphaFold is a generalized Bayesian model that explicitly defines a posterior distribution over structures, providing a deeper explanation of its success and a foundation for future model design. To demonstrate this framework with precision, we introduce a tractable synthetic model in which an angular random walk prior is updated with distance-based evidence via PK, directly mirroring AlphaFold's mechanism. This setting allows us to explore the probabilistic foundations of AlphaFold in a clear and interpretable way. Our work connects a landmark in protein structure prediction to a broader class of compositional deep generative models and points to new opportunities for principled probabilistic approaches.


From Alignment to Advancement: Bootstrapping Audio-Language Alignment with Synthetic Data

Abstract: Audio-aware large language models (ALLMs) have recently made great strides in understanding and processing audio inputs. These models are typically adapted from text-based large language models (LLMs) through additional training on audio-related tasks. This adaptation process presents two major limitations. First, ALLMs often suffer from catastrophic forgetting, where crucial textual capabilities like instruction-following are lost after training on audio data. In some cases, models may even hallucinate sounds that are not present in the input audio, raising concerns about reliability. Second, achieving cross-modal alignment between audio and language typically relies on large collections of task-specific question-answer pairs for instruction tuning, making it resource-intensive. To address these issues, previous works have leveraged the backbone LLMs to synthesize general-purpose, caption-style alignment data. In this paper, we propose a data generation framework that produces contrastive-like training data, designed to enhance ALLMs' ability to differentiate between present and absent sounds. We further extend our approach to multi-audio scenarios, enabling the model to either explain differences between audio inputs or produce unified captions that describe all inputs, thereby enhancing audio-language alignment. We refer to the entire ALLM training framework as bootstrapping audio-language alignment via synthetic data generation from backbone LLMs (BALSa). Experimental results indicate that our method effectively mitigates audio hallucinations while reliably maintaining strong performance on audio understanding and reasoning benchmarks, as well as instruction-following skills. Moreover, incorporating multi-audio training further enhances the model's comprehension and reasoning capabilities. Overall, BALSa offers an efficient and scalable approach to developing ALLMs.


Prot2Token: A Unified Framework for Protein Modeling via Next-Token Prediction

Abstract: The diverse nature of protein prediction tasks has traditionally necessitated specialized models, hindering the development of broadly applicable and computationally efficient Protein Language Models (PLMs). In this work, we introduce Prot2Token, a unified framework that overcomes these challenges by converting a wide spectrum of protein-related predictions-from sequence-level properties and residue-specific attributes to complex inter-protein interactions-into a standardized next-token prediction format. At its core, Prot2Token employs an autoregressive decoder, conditioned on embeddings from pre-trained protein encoders and guided by learnable task tokens, to perform diverse predictions. This architecture uniquely facilitates multi-task learning, enabling general-purpose decoders to generalize across five distinct categories. We present extensive experimental validation across a variety of benchmarks, demonstrating Prot2Token's predictive power in different types of protein-prediction tasks. In 3D structure prediction, Prot2Token delivers substantial speedups (up to 1000x faster than AlphaFold2 with MSA on the same hardware) while, across other numerous tasks, matching or surpassing specialized methods. Beyond that, we introduce an auxiliary self-supervised decoder pre-training approach to improve spatially sensitive task performance. Prot2Token thus offers a step towards standardizing biological prediction into a generative interface, promising to accelerate biological discovery and the development of novel therapeutics. The code is available at https://github.com/mahdip72/prot2token .

Mahdi Pourmirzaei
Farzaneh Esmaili
Salhuldin Alqarghuli
Mohammadreza Pourmirzaei
Ye Han
Kai Chen
Mohsen Rezaei
Duolin Wang
Dong Xu


Rethinking Text-based Protein Understanding: Retrieval or LLM?

Abstract: 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.

Juntong Wu
Zijing Liu
He Cao
Hao Li
Bin Feng
Zishan Shu
Ke Yu
Li Yuan
Yu Li

Conference on Empirical Methods in Natural Language Processing


Structure-Aligned Protein Language Model

Abstract: Protein language models (pLMs) pre-trained on vast protein sequence databases excel at various downstream tasks but often lack the structural knowledge essential for some biological applications. To address this, we introduce a method to enrich pLMs with structural knowledge by leveraging pre-trained protein graph neural networks (pGNNs). First, a latent-level contrastive learning task aligns residue representations from pLMs with those from pGNNs across multiple proteins, injecting inter-protein structural information. Additionally, a physical-level task integrates intra-protein information by training pLMs to predict structure tokens. Together, the proposed dual-task framework effectively incorporates both inter- and intra-protein structural knowledge into pLMs. Given the variability in the quality of protein structures in PDB, we further introduce a residue loss selection module that uses a small model trained on high-quality structures to select reliable yet challenging residue losses for the pLM to learn. Applying our structure alignment method as a simple, lightweight post-training step to the state-of-the-art ESM2 and AMPLIFY yields notable performance gains. These improvements are consistent across a wide range of tasks, including substantial gains in deep mutational scanning (DMS) fitness prediction and a 59% increase in P@L for ESM2 650M contact prediction on CASP16. Furthermore, we demonstrate that these performance gains are robust, scaling with model sizes from 8M to 650M and extending to different downstream tasks.

Can Chen
David Heurtel-Depeiges
Robert M. Vernon
Christopher James Langmead
Yoshua Bengio
Quentin Fournier


CausalVLBench: Benchmarking Visual Causal Reasoning in Large Vision-Language Models

Abstract: Large language models (LLMs) have shown remarkable ability in various language tasks, especially with their emergent in-context learning capability. Extending LLMs to incorporate visual inputs, large vision-language models (LVLMs) have shown impressive performance in tasks such as recognition and visual question answering (VQA). Despite increasing interest in the utility of LLMs in causal reasoning tasks such as causal discovery and counterfactual reasoning, there has been relatively little work showcasing the abilities of LVLMs on visual causal reasoning tasks. We take this opportunity to formally introduce a comprehensive causal reasoning benchmark for multi-modal in-context learning from LVLMs. Our CausalVLBench encompasses three representative tasks: causal structure inference, intervention target prediction, and counterfactual prediction. We evaluate the ability of state-of-the-art open-source LVLMs on our causal reasoning tasks across three causal representation learning datasets and demonstrate their fundamental strengths and weaknesses. We hope that our benchmark elucidates the drawbacks of existing vision-language models and motivates new directions and paradigms in improving the visual causal reasoning abilities of LVLMs.

Aneesh Komanduri
Karuna Bhaila
Xintao Wu


Modeling and prediction of mutation fitness on protein functionality with structural information using high-dimensional Potts model

Abstract: Quantifying the effects of amino acid mutations in proteins presents a significant challenge due to the vast combinations of residue sites and amino acid types, making experimental approaches costly and time-consuming. The Potts model has been used to address this challenge, with parameters capturing evolutionary dependency between residue sites within a protein family. However, existing methods often use the mean-field approximation to reduce computational demands, which lacks provable guarantees and overlooks critical structural information for assessing mutation effects. We propose a new framework for analyzing protein sequences using the Potts model with node-wise high-dimensional multinomial regression. Our method identifies key residue interactions and important amino acids, quantifying mutation effects through evolutionary energy derived from model parameters. It encourages sparsity in both site-wise and amino acid-wise dependencies through element-wise and group sparsity. We have established, for the first time to our knowledge, the $\ell_2$ convergence rate for estimated parameters in the high-dimensional Potts model using sparse group Lasso, matching the existing minimax lower bound for high-dimensional linear models with a sparse group structure, up to a factor depending only on the multinomial nature of the Potts model. This theoretical guarantee enables accurate quantification of estimated energy changes. Additionally, we incorporate structural data into our model by applying penalty weights across site pairs. Our method outperforms others in predicting mutation fitness, as demonstrated by comparisons with high-throughput mutagenesis experiments across 12 protein families.

Bingying Dai
Yinan Lin
Kejue Jia
Zhao Ren
Wen Zhou


DS-ProGen: A Dual-Structure Deep Language Model for Functional Protein Design

Abstract: Inverse Protein Folding (IPF) is a critical subtask in the field of protein design, aiming to engineer amino acid sequences capable of folding correctly into a specified three-dimensional (3D) conformation. Although substantial progress has been achieved in recent years, existing methods generally rely on either backbone coordinates or molecular surface features alone, which restricts their ability to fully capture the complex chemical and geometric constraints necessary for precise sequence prediction. To address this limitation, we present DS-ProGen, a dual-structure deep language model for functional protein design, which integrates both backbone geometry and surface-level representations. By incorporating backbone coordinates as well as surface chemical and geometric descriptors into a next-amino-acid prediction paradigm, DS-ProGen is able to generate functionally relevant and structurally stable sequences while satisfying both global and local conformational constraints. On the PRIDE dataset, DS-ProGen attains the current state-of-the-art recovery rate of 61.47%, demonstrating the synergistic advantage of multi-modal structural encoding in protein design. Furthermore, DS-ProGen excels in predicting interactions with a variety of biological partners, including ligands, ions, and RNA, confirming its robust functional retention capabilities.

Yanting Li
Jiyue Jiang
Zikang Wang
Ziqian Lin
Dongchen He
Yuheng Shan
Yanruisheng Shao
Jiayi Li
Xiangyu Shi
Jiuming Wang
Yanyu Chen
Yimin Fan
Han Li
Yu Li


mCLM: A Modular Chemical Language Model that Generates Functional and Makeable Molecules

Abstract: Despite their ability to understand chemical knowledge, large language models (LLMs) remain limited in their capacity to propose novel molecules with desired functions (e.g., drug-like properties). In addition, the molecules that LLMs propose can often be challenging to make, and are almost never compatible with automated synthesis approaches. To better enable the discovery of functional small molecules, LLMs need to learn a new molecular language that is more effective in predicting properties and inherently synced with automated synthesis technology. Current molecule LLMs are limited by representing molecules based on atoms. In this paper, we argue that just like tokenizing texts into meaning-bearing (sub-)word tokens instead of characters, molecules should be tokenized at the level of functional building blocks, i.e., parts of molecules that bring unique functions and serve as effective building blocks for real-world automated laboratory synthesis. This motivates us to propose mCLM, a modular Chemical-Language Model that comprises a bilingual language model that understands both natural language descriptions of functions and molecular blocks. mCLM front-loads synthesizability considerations while improving the predicted functions of molecules in a principled manner. Experiments on FDA-approved drugs showed that mCLM is capable of significantly improving chemical functions. mCLM, with only 3B parameters, also achieves improvements in synthetic accessibility relative to 7 other leading generative AI methods including GPT-5. When tested on 122 out-of-distribution medicines using only building blocks/tokens that are compatible with automated modular synthesis, mCLM outperforms all baselines in property scores and synthetic accessibility. mCLM can also reason on multiple functions and iteratively self-improve to rescue drug candidates that failed late in clinical trials ("fallen angels").

Carl Edwards
Chi Han
Gawon Lee
Thao Nguyen
Sara Szymkuć
Chetan Kumar Prasad
Bowen Jin
Jiawei Han
Ying Diao
Ge Liu
Hao Peng
Bartosz A. Grzybowski
Martin D. Burke
Heng Ji


Retrospex: Language Agent Meets Offline Reinforcement Learning Critic

Abstract: Large Language Models (LLMs) possess extensive knowledge and commonsense reasoning capabilities, making them valuable for creating powerful agents. However, existing LLM agent frameworks have not fully utilized past experiences for improvement. This work introduces a new LLM-based agent framework called Retrospex, which addresses this challenge by analyzing past experiences in depth. Unlike previous approaches, Retrospex does not directly integrate experiences into the LLM's context. Instead, it combines the LLM's action likelihood with action values estimated by a Reinforcement Learning (RL) Critic, which is trained on past experiences through an offline ''retrospection'' process. Additionally, Retrospex employs a dynamic action rescoring mechanism that increases the importance of experience-based values for tasks that require more interaction with the environment. We evaluate Retrospex in ScienceWorld, ALFWorld and Webshop environments, demonstrating its advantages over strong, contemporary baselines.

Yufei Xiang
Yiqun Shen
Yeqin Zhang
Cam-Tu Nguyen


Prot2Text-V2: Protein Function Prediction with Multimodal Contrastive Alignment

Abstract: Predicting protein function from sequence is a central challenge in computational biology. While existing methods rely heavily on structured ontologies or similarity-based techniques, they often lack the flexibility to express structure-free functional descriptions and novel biological functions. In this work, we introduce Prot2Text-V2, a novel multimodal sequence-to-text model that generates free-form natural language descriptions of protein function directly from amino acid sequences. Our method combines a protein language model as a sequence encoder (ESM-3B) and a decoder-only language model (LLaMA-3.1-8B-Instruct) through a lightweight nonlinear modality projector. A key innovation is our Hybrid Sequence-level Contrastive Alignment Learning (H-SCALE), which improves cross-modal learning by matching mean- and std-pooled protein embeddings with text representations via contrastive loss. After the alignment phase, we apply instruction-based fine-tuning using LoRA on the decoder to teach the model how to generate accurate protein function descriptions conditioned on the protein sequence. We train Prot2Text-V2 on about 250K curated entries from SwissProt and evaluate it under low-homology conditions, where test sequences have low similarity with training samples. Prot2Text-V2 consistently outperforms traditional and LLM-based baselines across various metrics.

Xiao Fei
Michail Chatzianastasis
Sarah Almeida Carneiro
Hadi Abdine
Lawrence P. Petalidis
Michalis Vazirgiannis


PSBench: a large-scale benchmark for estimating the accuracy of protein complex structural models

Abstract: Predicting protein complex structures is essential for protein function analysis, protein design, and drug discovery. While AI methods like AlphaFold can predict accurate structural models for many protein complexes, reliably estimating the quality of these predicted models (estimation of model accuracy, or EMA) for model ranking and selection remains a major challenge. A key barrier to developing effective machine learning-based EMA methods is the lack of large, diverse, and well-annotated datasets for training and evaluation. To address this gap, we introduce PSBench, a benchmark suite comprising four large-scale, labeled datasets generated during the 15th and 16th community-wide Critical Assessment of Protein Structure Prediction (CASP15 and CASP16). PSBench includes over one million structural models covering a wide range of protein sequence lengths, complex stoichiometries, functional classes, and modeling difficulties. Each model is annotated with multiple complementary quality scores at the global, local, and interface levels. PSBench also provides multiple evaluation metrics and baseline EMA methods to facilitate rigorous comparisons. To demonstrate PSBench's utility, we trained and evaluated GATE, a graph transformer-based EMA method, on the CASP15 data. GATE was blindly tested in CASP16 (2024), where it ranked among the top-performing EMA methods. These results highlight PSBench as a valuable resource for advancing EMA research in protein complex modeling. PSBench is publicly available at: https://github.com/BioinfoMachineLearning/PSBench.


Protein FID: Improved Evaluation of Protein Structure Generative Models

Abstract: Protein structure generative models have seen a recent surge of interest, but meaningfully evaluating them computationally is an active area of research. While current metrics have driven useful progress, they do not capture how well models sample the design space represented by the training data. We argue for a protein Frechet Inception Distance (FID) metric to supplement current evaluations with a measure of distributional similarity in a semantically meaningful latent space. Our FID behaves desirably under protein structure perturbations and correctly recapitulates similarities between protein samples: it correlates with optimal transport distances and recovers FoldSeek clusters and the CATH hierarchy. Evaluating current protein structure generative models with FID shows that they fall short of modeling the distribution of PDB proteins.

Felix Faltings
Hannes Stark
Tommi Jaakkola
Regina Barzilay


LightNobel: Improving Sequence Length Limitation in Protein Structure Prediction Model via Adaptive Activation Quantization

Abstract: Recent advances in Protein Structure Prediction Models (PPMs), such as AlphaFold2 and ESMFold, have revolutionized computational biology by achieving unprecedented accuracy in predicting three-dimensional protein folding structures. However, these models face significant scalability challenges, particularly when processing proteins with long amino acid sequences (e.g., sequence length > 1,000). The primary bottleneck that arises from the exponential growth in activation sizes is driven by the unique data structure in PPM, which introduces an additional dimension that leads to substantial memory and computational demands. These limitations have hindered the effective scaling of PPM for real-world applications, such as analyzing large proteins or complex multimers with critical biological and pharmaceutical relevance. In this paper, we present LightNobel, the first hardware-software co-designed accelerator developed to overcome scalability limitations on the sequence length in PPM. At the software level, we propose Token-wise Adaptive Activation Quantization (AAQ), which leverages unique token-wise characteristics, such as distogram patterns in PPM activations, to enable fine-grained quantization techniques without compromising accuracy. At the hardware level, LightNobel integrates the multi-precision reconfigurable matrix processing unit (RMPU) and versatile vector processing unit (VVPU) to enable the efficient execution of AAQ. Through these innovations, LightNobel achieves up to 8.44x, 8.41x speedup and 37.29x, 43.35x higher power efficiency over the latest NVIDIA A100 and H100 GPUs, respectively, while maintaining negligible accuracy loss. It also reduces the peak memory requirement up to 120.05x in PPM, enabling scalable processing for proteins with long sequences.

International Symposium on Computer Architecture


Exploring zero-shot structure-based protein fitness prediction

Abstract: The ability to make zero-shot predictions about the fitness consequences of protein sequence changes with pre-trained machine learning models enables many practical applications. Such models can be applied for downstream tasks like genetic variant interpretation and protein engineering without additional labeled data. The advent of capable protein structure prediction tools has led to the availability of orders of magnitude more precomputed predicted structures, giving rise to powerful structure-based fitness prediction models. Through our experiments, we assess several modeling choices for structure-based models and their effects on downstream fitness prediction. Zero-shot fitness prediction models can struggle to assess the fitness landscape within disordered regions of proteins, those that lack a fixed 3D structure. We confirm the importance of matching protein structures to fitness assays and find that predicted structures for disordered regions can be misleading and affect predictive performance. Lastly, we evaluate an additional structure-based model on the ProteinGym substitution benchmark and show that simple multi-modal ensembles are strong baselines.


Enhancing TCR-Peptide Interaction Prediction with Pretrained Language Models and Molecular Representations

Abstract: Understanding the binding specificity between T-cell receptors (TCRs) and peptide-major histocompatibility complexes (pMHCs) is central to immunotherapy and vaccine development. However, current predictive models struggle with generalization, especially in data-scarce settings and when faced with novel epitopes. We present LANTERN (Large lAnguage model-powered TCR-Enhanced Recognition Network), a deep learning framework that combines large-scale protein language models with chemical representations of peptides. By encoding TCR \b{eta}-chain sequences using ESM-1b and transforming peptide sequences into SMILES strings processed by MolFormer, LANTERN captures rich biological and chemical features critical for TCR-peptide recognition. Through extensive benchmarking against existing models such as ChemBERTa, TITAN, and NetTCR, LANTERN demonstrates superior performance, particularly in zero-shot and few-shot learning scenarios. Our model also benefits from a robust negative sampling strategy and shows significant clustering improvements via embedding analysis. These results highlight the potential of LANTERN to advance TCR-pMHC binding prediction and support the development of personalized immunotherapies.

Cong Qi
Hanzhang Fang
Siqi jiang
Tianxing Hu
Zhi Wei


Hierarchical protein backbone generation with latent and structure diffusion

Abstract: We propose a hierarchical protein backbone generative model that separates coarse and fine-grained details. Our approach called LSD consists of two stages: sampling latents which are decoded into a contact map then sampling atomic coordinates conditioned on the contact map. LSD allows new ways to control protein generation towards desirable properties while scaling to large datasets. In particular, the AlphaFold DataBase (AFDB) is appealing due as its diverse structure topologies but suffers from poor designability. We train LSD on AFDB and show latent diffusion guidance towards AlphaFold2 Predicted Alignment Error and long range contacts can explicitly balance designability, diversity, and noveltys in the generated samples. Our results are competitive with structure diffusion models and outperforms prior latent diffusion models.

Jason Yim
Marouane Jaakik
Ge Liu
Jacob Gershon
Karsten Kreis
David Baker
Regina Barzilay
Tommi Jaakkola


Mass Balance Approximation of Unfolding Improves Potential-Like Methods for Protein Stability Predictions

Abstract: The prediction of protein stability changes following single-point mutations plays a pivotal role in computational biology, particularly in areas like drug discovery, enzyme reengineering, and genetic disease analysis. Although deep-learning strategies have pushed the field forward, their use in standard workflows remains limited due to resource demands. Conversely, potential-like methods are fast, intuitive, and efficient. Yet, these typically estimate Gibbs free energy shifts without considering the free-energy variations in the unfolded protein state, an omission that may breach mass balance and diminish accuracy. This study shows that incorporating a mass-balance correction (MBC) to account for the unfolded state significantly enhances these methods. While many machine learning models partially model this balance, our analysis suggests that a refined representation of the unfolded state may improve the predictive performance.

Ivan Rossi
Guido Barducci
Tiziana Sanavia
Paola Turina
Emidio Capriotti
Piero Fariselli

Biology
Computer Science
Physics
Medicine


Prot42: a Novel Family of Protein Language Models for Target-aware Protein Binder Generation

Abstract: Unlocking the next generation of biotechnology and therapeutic innovation demands overcoming the inherent complexity and resource-intensity of conventional protein engineering methods. Recent GenAI-powered computational techniques often rely on the availability of the target protein's 3D structures and specific binding sites to generate high-affinity binders, constraints exhibited by models such as AlphaProteo and RFdiffusion. In this work, we explore the use of Protein Language Models (pLMs) for high-affinity binder generation. We introduce Prot42, a novel family of Protein Language Models (pLMs) pretrained on vast amounts of unlabeled protein sequences. By capturing deep evolutionary, structural, and functional insights through an advanced auto-regressive, decoder-only architecture inspired by breakthroughs in natural language processing, Prot42 dramatically expands the capabilities of computational protein design based on language only. Remarkably, our models handle sequences up to 8,192 amino acids, significantly surpassing standard limitations and enabling precise modeling of large proteins and complex multi-domain sequences. Demonstrating powerful practical applications, Prot42 excels in generating high-affinity protein binders and sequence-specific DNA-binding proteins. Our innovative models are publicly available, offering the scientific community an efficient and precise computational toolkit for rapid protein engineering.

Mohammad Amaan Sayeed
Engin Tekin
Maryam Nadeem
Nancy A. ElNaker
Aahan Singh
Natalia Vassilieva
Boulbaba Ben Amor


Redefining technology for indigenous languages

Abstract: In this paper, we offer an overview of indigenous languages, identifying the causes of their devaluation and the need for legislation on language rights. We review the technologies used to revitalize these languages, finding that when they come from outside, they often have the opposite effect to what they seek; however, when developed from within communities, they become powerful instruments of expression. We propose that the inclusion of Indigenous knowledge in large language models (LLMs) will enrich the technological landscape, but must be done in a participatory environment that encourages the exchange of knowledge.

Silvia Fernandez-Sabido
Laura Peniche-Sabido


Deep Learning-Driven Protein Structure Prediction and Design: Key Model Developments by Nobel Laureates and Multi-Domain Applications

Abstract: This systematic review outlines pivotal advancements in deep learning-driven protein structure prediction and design, focusing on four core models-AlphaFold, RoseTTAFold, RFDiffusion, and ProteinMPNN-developed by 2024 Nobel Laureates in Chemistry: David Baker, Demis Hassabis, and John Jumper. We analyze their technological iterations and collaborative design paradigms, emphasizing breakthroughs in atomic-level structural accuracy, functional protein engineering, and multi-component biomolecular interaction modeling. Key innovations include AlphaFold3's diffusion-based framework for unified biomolecular prediction, RoseTTAFold's three-track architecture integrating sequence and spatial constraints, RFDiffusion's denoising diffusion for de novo protein generation, and ProteinMPNN's inverse folding for sequence-structure co-optimization. Despite transformative progress in applications such as binder design, nanomaterials, and enzyme engineering, challenges persist in dynamic conformational sampling, multimodal data integration, and generalization to non-canonical targets. We propose future directions, including hybrid physics-AI frameworks and multimodal learning, to bridge gaps between computational design and functional validation in cellular environments.


Whisper-LM: Improving ASR Models with Language Models for Low-Resource Languages

Abstract: Automatic speech recognition systems have undoubtedly advanced with the integration of multilingual and multitask models such as Whisper, which have shown a promising ability to understand and process speech across a wide range of languages. Despite their robustness, these models often fall short in handling the linguistic distinctions of minority languages. This study addresses this gap by integrating traditional and novel language models with fine-tuned Whisper models to raise their performance in less commonly studied languages. Through rigorous fine-tuning and evaluation across multiple datasets, we demonstrate substantial improvements in word error rate, particularly in low-resource scenarios. Our approach not only does take advantage of the extensive data Whisper was pre-trained on, but also complements its linguistic adaptability by incorporating language models. We obtained improvements up to 51% for in-distribution datasets and up to 34% for out-of-distribution sentences using statistical language models, while large language models provided moderate but consistently robust improvement across diverse linguistic contexts. The findings reveal that, while the integration reliably benefits all model sizes, the extent of improvement varies, highlighting the importance of optimized language model parameters. Finally, we emphasize the importance of selecting appropriate evaluation parameters when reporting the results using transformer-based ASR models. In summary, this research clears the way for more inclusive ASR technologies that perform better across languages by enriching their linguistic knowledge. For further implementation details of this study, the technical documentation and source code are available at http://www.github.com/hitz-zentroa/whisper-lm.

Xabier de Zuazo
Eva Navas
Ibon Saratxaga
Inma Hernáez Rioja


MSNGO: multi-species protein function annotation based on 3D protein structure and network propagation

Abstract: Motivation: In recent years, protein function prediction has broken through the bottleneck of sequence features, significantly improving prediction accuracy using high-precision protein structures predicted by AlphaFold2. While single-species protein function prediction methods have achieved remarkable success, multi-species protein function prediction methods are still in the stage of using PPI networks and sequence features. Providing effective cross-species label propagation for species with sparse protein annotations remains a challenging issue. To address this problem, we propose the MSNGO model, which integrates structural features and network propagation methods. Our validation shows that using structural features can significantly improve the accuracy of multi-species protein function prediction. Results: We employ graph representation learning techniques to extract amino acid representations from protein structure contact maps and train a structural model using a graph convolution pooling module to derive protein-level structural features. After incorporating the sequence features from ESM-2, we apply a network propagation algorithm to aggregate information and update node representations within a heterogeneous network. The results demonstrate that MSNGO outperforms previous multi-species protein function prediction methods that rely on sequence features and PPI networks. Availability: https://github.com/blingbell/MSNGO.

Beibei Wang
Boyue Cui
Shiqu Chen
Xuan Wang
Yadong Wang
Junyi Li


How do language models learn facts? Dynamics, curricula and hallucinations

Abstract: Large language models accumulate vast knowledge during pre-training, yet the dynamics governing this acquisition remain poorly understood. This work investigates the learning dynamics of language models on a synthetic factual recall task, uncovering three key findings: First, language models learn in three phases, exhibiting a performance plateau before acquiring precise factual knowledge. Mechanistically, this plateau coincides with the formation of attention-based circuits that support recall. Second, the training data distribution significantly impacts learning dynamics, as imbalanced distributions lead to shorter plateaus. Finally, hallucinations emerge simultaneously with knowledge, and integrating new knowledge into the model through fine-tuning is challenging, as it quickly corrupts its existing parametric memories. Our results emphasize the importance of data distribution in knowledge acquisition and suggest novel data scheduling strategies to accelerate neural network training.

Nicolas Zucchet
Jörg Bornschein
Stephanie Chan
Andrew Lampinen
Razvan Pascanu
Soham De


Untangling the Influence of Typology, Data and Model Architecture on Ranking Transfer Languages for Cross-Lingual POS Tagging

Abstract: Cross-lingual transfer learning is an invaluable tool for overcoming data scarcity, yet selecting a suitable transfer language remains a challenge. The precise roles of linguistic typology, training data, and model architecture in transfer language choice are not fully understood. We take a holistic approach, examining how both dataset-specific and fine-grained typological features influence transfer language selection for part-of-speech tagging, considering two different sources for morphosyntactic features. While previous work examines these dynamics in the context of bilingual biLSTMS, we extend our analysis to a more modern transfer learning pipeline: zero-shot prediction with pretrained multilingual models. We train a series of transfer language ranking systems and examine how different feature inputs influence ranker performance across architectures. Word overlap, type-token ratio, and genealogical distance emerge as top features across all architectures. Our findings reveal that a combination of typological and dataset-dependent features leads to the best rankings, and that good performance can be obtained with either feature group on its own.

Enora Rice
Ali Marashian
Hannah Haynie
Katharina von der Wense
Alexis Palmer


An Energy-Adaptive Elastic Equivariant Transformer Framework for Protein Structure Representation

Abstract: Structure-informed protein representation learning is essential for effective protein function annotation and \textit{de novo} design. However, the presence of inherent noise in both crystal and AlphaFold-predicted structures poses significant challenges for existing methods in learning robust protein representations. To address these issues, we propose a novel equivariant Transformer-State Space Model(SSM) hybrid framework, termed $E^3$former, designed for efficient protein representation. Our approach uses energy function-based receptive fields to construct proximity graphs and incorporates an equivariant high-tensor-elastic selective SSM within the transformer architecture. These components enable the model to adapt to complex atom interactions and extract geometric features with higher signal-to-noise ratios. Empirical results demonstrate that our model outperforms existing methods in structure-intensive tasks, such as inverse folding and binding site prediction, particularly when using predicted structures, owing to its enhanced tolerance to data deviation and noise. Our approach offers a novel perspective for conducting biological function research and drug discovery using noisy protein structure data.

Zhongyue Zhang
Runze Ma
Yanjie Huang
Shuangjia Zheng


VenusFactory: A Unified Platform for Protein Engineering Data Retrieval and Language Model Fine-Tuning

Abstract: Natural language processing (NLP) has significantly influenced scientific domains beyond human language, including protein engineering, where pre-trained protein language models (PLMs) have demonstrated remarkable success. However, interdisciplinary adoption remains limited due to challenges in data collection, task benchmarking, and application. This work presents VenusFactory, a versatile engine that integrates biological data retrieval, standardized task benchmarking, and modular fine-tuning of PLMs. VenusFactory supports both computer science and biology communities with choices of both a command-line execution and a Gradio-based no-code interface, integrating $40+$ protein-related datasets and $40+$ popular PLMs. All implementations are open-sourced on https://github.com/tyang816/VenusFactory.

Yang Tan
Chen Liu
Jingyuan Gao
Banghao Wu
Mingchen Li
Ruilin Wang
Lingrong Zhang
Huiqun Yu
Guisheng Fan
Liang Hong
Bingxin Zhou


Advanced Deep Learning Methods for Protein Structure Prediction and Design

Abstract: After AlphaFold won the Nobel Prize, protein prediction with deep learning once again became a hot topic. We comprehensively explore advanced deep learning methods applied to protein structure prediction and design. It begins by examining recent innovations in prediction architectures, with detailed discussions on improvements such as diffusion based frameworks and novel pairwise attention modules. The text analyses key components including structure generation, evaluation metrics, multiple sequence alignment processing, and network architecture, thereby illustrating the current state of the art in computational protein modelling. Subsequent chapters focus on practical applications, presenting case studies that range from individual protein predictions to complex biomolecular interactions. Strategies for enhancing prediction accuracy and integrating deep learning techniques with experimental validation are thoroughly explored. The later sections review the industry landscape of protein design, highlighting the transformative role of artificial intelligence in biotechnology and discussing emerging market trends and future challenges. Supplementary appendices provide essential resources such as databases and open source tools, making this volume a valuable reference for researchers and students.

Yichao Zhang
Ningyuan Deng
Xinyuan Song
Ziqian Bi
Tianyang Wang
Zheyu Yao
Keyu Chen
Ming Li
Qian Niu
Junyu Liu
Benji Peng
Sen Zhang
Ming Liu
Li Zhang
Xuanhe Pan
Jinlang Wang
Pohsun Feng
Yizhu Wen
Lawrence KQ Yan
Hongming Tseng
Yan Zhong
Yunze Wang
Ziyuan Qin
Bowen Jing
Junjie Yang
Jun Zhou
Chia Xin Liang
Junhao Song


Towards Interpretable Protein Structure Prediction with Sparse Autoencoders

Abstract: Protein language models have revolutionized structure prediction, but their nonlinear nature obscures how sequence representations inform structure prediction. While sparse autoencoders (SAEs) offer a path to interpretability here by learning linear representations in high-dimensional space, their application has been limited to smaller protein language models unable to perform structure prediction. In this work, we make two key advances: (1) we scale SAEs to ESM2-3B, the base model for ESMFold, enabling mechanistic interpretability of protein structure prediction for the first time, and (2) we adapt Matryoshka SAEs for protein language models, which learn hierarchically organized features by forcing nested groups of latents to reconstruct inputs independently. We demonstrate that our Matryoshka SAEs achieve comparable or better performance than standard architectures. Through comprehensive evaluations, we show that SAEs trained on ESM2-3B significantly outperform those trained on smaller models for both biological concept discovery and contact map prediction. Finally, we present an initial case study demonstrating how our approach enables targeted steering of ESMFold predictions, increasing structure solvent accessibility while fixing the input sequence. To facilitate further investigation by the broader community, we open-source our code, dataset, pretrained models https://github.com/johnyang101/reticular-sae , and visualizer https://sae.reticular.ai .

Nithin Parsan
David J. Yang
John J. Yang


ProtTeX: Structure-In-Context Reasoning and Editing of Proteins with Large Language Models

Abstract: Large language models have made remarkable progress in the field of molecular science, particularly in understanding and generating functional small molecules. This success is largely attributed to the effectiveness of molecular tokenization strategies. In protein science, the amino acid sequence serves as the sole tokenizer for LLMs. However, many fundamental challenges in protein science are inherently structure-dependent. The absence of structure-aware tokens significantly limits the capabilities of LLMs for comprehensive biomolecular comprehension and multimodal generation. To address these challenges, we introduce a novel framework, ProtTeX, which tokenizes the protein sequences, structures, and textual information into a unified discrete space. This innovative approach enables joint training of the LLM exclusively through the Next-Token Prediction paradigm, facilitating multimodal protein reasoning and generation. ProtTeX enables general LLMs to perceive and process protein structures through sequential text input, leverage structural information as intermediate reasoning components, and generate or manipulate structures via sequential text output. Experiments demonstrate that our model achieves significant improvements in protein function prediction, outperforming the state-of-the-art domain expert model with a twofold increase in accuracy. Our framework enables high-quality conformational generation and customizable protein design. For the first time, we demonstrate that by adopting the standard training and inference pipelines from the LLM domain, ProtTeX empowers decoder-only LLMs to effectively address diverse spectrum of protein-related tasks.

Zicheng Ma
Chuanliu Fan
Zhicong Wang
Zhenyu Chen
Xiaohan Lin
Yanheng Li
Shihao Feng
Jun Zhang
Ziqiang Cao
Yi Qin Gao

Journal of Chemical Information and Modeling


Gender Encoding Patterns in Pretrained Language Model Representations

Abstract: Gender bias in pretrained language models (PLMs) poses significant social and ethical challenges. Despite growing awareness, there is a lack of comprehensive investigation into how different models internally represent and propagate such biases. This study adopts an information-theoretic approach to analyze how gender biases are encoded within various encoder-based architectures. We focus on three key aspects: identifying how models encode gender information and biases, examining the impact of bias mitigation techniques and fine-tuning on the encoded biases and their effectiveness, and exploring how model design differences influence the encoding of biases. Through rigorous and systematic investigation, our findings reveal a consistent pattern of gender encoding across diverse models. Surprisingly, debiasing techniques often exhibit limited efficacy, sometimes inadvertently increasing the encoded bias in internal representations while reducing bias in model output distributions. This highlights a disconnect between mitigating bias in output distributions and addressing its internal representations. This work provides valuable guidance for advancing bias mitigation strategies and fostering the development of more equitable language models.


From Language to Cognition: How LLMs Outgrow the Human Language Network

Abstract: Large language models (LLMs) exhibit remarkable similarity to neural activity in the human language network. However, the key properties of language shaping brain-like representations, and their evolution during training as a function of different tasks remain unclear. We here benchmark 34 training checkpoints spanning 300B tokens across 8 different model sizes to analyze how brain alignment relates to linguistic competence. Specifically, we find that brain alignment tracks the development of formal linguistic competence -- i.e., knowledge of linguistic rules -- more closely than functional linguistic competence. While functional competence, which involves world knowledge and reasoning, continues to develop throughout training, its relationship with brain alignment is weaker, suggesting that the human language network primarily encodes formal linguistic structure rather than broader cognitive functions. We further show that model size is not a reliable predictor of brain alignment when controlling for feature size and find that the correlation between next-word prediction, behavioral alignment and brain alignment fades once models surpass human language proficiency. Finally, using the largest set of rigorous neural language benchmarks to date, we show that language brain alignment benchmarks remain unsaturated, highlighting opportunities for improving future models. Taken together, our findings suggest that the human language network is best modeled by formal, rather than functional, aspects of language.

Badr AlKhamissi
Greta Tuckute
Yingtian Tang
Taha Binhuraib
Antoine Bosselut
Martin Schrimpf


A Model-Centric Review of Deep Learning for Protein Design

Abstract: Deep learning has transformed protein design, enabling accurate structure prediction, sequence optimization, and de novo protein generation. Advances in single-chain protein structure prediction via AlphaFold2, RoseTTAFold, ESMFold, and others have achieved near-experimental accuracy, inspiring successive work extended to biomolecular complexes via AlphaFold Multimer, RoseTTAFold All-Atom, AlphaFold 3, Chai-1, Boltz-1 and others. Generative models such as ProtGPT2, ProteinMPNN, and RFdiffusion have enabled sequence and backbone design beyond natural evolution-based limitations. More recently, joint sequence-structure co-design models, including ESM3, have integrated both modalities into a unified framework, resulting in improved designability. Despite these advances, challenges still exist pertaining to modeling sequence-structure-function relationships and ensuring robust generalization beyond the regions of protein space spanned by the training data. Future advances will likely focus on joint sequence-structure-function co-design frameworks that are able to model the fitness landscape more effectively than models that treat these modalities independently. Current capabilities, coupled with the dizzying rate of progress, suggest that the field will soon enable rapid, rational design of proteins with tailored structures and functions that transcend the limitations imposed by natural evolution. In this review, we discuss the current capabilities of deep learning methods for protein design, focusing on some of the most revolutionary and capable models with respect to their functionality and the applications that they enable, leading up to the current challenges of the field and the optimal path forward.

Gregory W. Kyro
Tianyin Qiu
Victor S. Batista


Leveraging Retrieval-Augmented Generation and Large Language Models to Predict SERCA-Binding Protein Fragments from Cardiac Proteomics Data

Abstract: Large language models (LLMs) have shown promise in various natural language processing tasks, including their application to proteomics data to classify protein fragments. In this study, we curated a limited mass spectrometry dataset with 1000s of protein fragments, consisting of proteins that appear to be attached to the endoplasmic reticulum in cardiac cells, of which a fraction was cloned and characterized for their impact on SERCA, an ER calcium pump. With this limited dataset, we sought to determine whether LLMs could correctly predict whether a new protein fragment could bind SERCA, based only on its sequence and a few biophysical characteristics, such as hydrophobicity, determined from that sequence. To do so, we generated random sequences based on cloned fragments, embedded the fragments into a retrieval augmented generation (RAG) database to group them by similarity, then fine-tuned large language model (LLM) prompts to predict whether a novel sequence could bind SERCA. We benchmarked this approach using multiple open-source LLMs, namely the Meta/llama series, and embedding functions commonly available on the Huggingface repository. We then assessed the generalizability of this approach in classifying novel protein fragments from mass spectrometry that were not initially cloned for functional characterization. By further tuning the prompt to account for motifs, such as ER retention sequences, we improved the classification accuracy by and identified several proteins predicted to localize to the endoplasmic reticulum and bind SERCA, including Ribosomal Protein L2 and selenoprotein S. Although our results were based on proteomics data from cardiac cells, our approach demonstrates the potential of LLMs in identifying novel protein interactions and functions with very limited proteomic data.

Taylor A Phillips
Alejandro W. Huskey
Patrick T. Huskey
Seth L. Robia
Peter M. Kekenes-Huskey


Characterizing the Conformational States of G Protein Coupled Receptors Generated with AlphaFold

Abstract: G-Protein Coupled Receptors (GPCRs) are integral to numerous physiological processes and are the target of approximately one-third of FDA-approved therapeutics. Despite their significance, only a limited subset of GPCRs has been successfully targeted, primarily due to challenges in accurately modeling their structures. AlphaFold, a state-of-the-art deep learning model, has demonstrated remarkable capability in predicting protein structures with high accuracy. This study conducts an evaluation of AlphaFold performance in predicting GPCR structures and their conformational states by comparing its predictions to experimentally determined structures using metrics such as average deformation between alpha carbon atoms and the Helix 3 - Helix 6 (H3-H6) distance. Our analysis reveals that both AlphaFold 2 (AF2) and AlphaFold 3 (AF3) produce more accurate predictions for GPCRs in inactive conformations, with lower activity levels correlating with smaller deformations. Conversely, higher activity levels are associated with increased variability in AlphaFold performance due to difficulties with accurately predicting conformational changes upon GPCR activation and ligand binding. Additionally, AlphaFold performance varies across different GPCR classes, influenced by the availability and quality of training data as well as the structural complexity and diversity of the receptors. These findings demonstrate the potential of AlphaFold in advancing drug discovery efforts, while also highlighting the necessity for continued refinement to enhance predictive accuracy for active conformations.

Garima Chib
Parisa Mollaei
Amir Barati Farimani


Child vs. machine language learning: Can the logical structure of human language unleash LLMs?

Abstract: We argue that human language learning proceeds in a manner that is different in nature from current approaches to training LLMs, predicting a difference in learning biases. We then present evidence from German plural formation by LLMs that confirm our hypothesis that even very powerful implementations produce results that miss aspects of the logic inherent to language that humans have no problem with. We conclude that attention to the different structures of human language and artificial neural networks is likely to be an avenue to improve LLM performance.

Uli Sauerland
Celia Matthaei
Felix Salfner


Integrating protein sequence embeddings with structure via graph-based deep learning for single-residue property prediction

Abstract: Understanding the intertwined contributions of amino acid sequence and spatial structure is essential to explain protein behaviour. Here, we introduce INFUSSE (Integrated Network Framework Unifying Structure and Sequence Embeddings), a deep learning framework for the prediction of single-residue properties that combines fine-tuning of sequence embeddings derived from a Large Language Model with the inclusion of graph-based representations of protein structures via a diffusive Graph Convolutional Network. To illustrate the benefits of jointly leveraging sequence and structure, we apply INFUSSE to the prediction of B-factors in antibodies, a residue property that reflects the local flexibility shaped by biochemical and structural constraints in these highly variable and dynamic proteins. Using a dataset of 1510 antibody and antibody-antigen complexes from the database SAbDab, we show that INFUSSE improves performance over current machine learning (ML) methods based on sequence or structure alone, and allows for the systematic disentanglement of sequence and structure contributions to the performance. Our results show that adding structural information via geometric graphs enhances predictions especially for intrinsically disordered regions, protein-protein interaction sites, and highly variable amino acid positions -- all key structural features for antibody function which are not well captured by purely sequence-based ML descriptions.

Kevin Michalewicz
Mauricio Barahona
Barbara Bravi


Protein Large Language Models: A Comprehensive Survey

Abstract: Protein-specific large language models (Protein LLMs) are revolutionizing protein science by enabling more efficient protein structure prediction, function annotation, and design. While existing surveys focus on specific aspects or applications, this work provides the first comprehensive overview of Protein LLMs, covering their architectures, training datasets, evaluation metrics, and diverse applications. Through a systematic analysis of over 100 articles, we propose a structured taxonomy of state-of-the-art Protein LLMs, analyze how they leverage large-scale protein sequence data for improved accuracy, and explore their potential in advancing protein engineering and biomedical research. Additionally, we discuss key challenges and future directions, positioning Protein LLMs as essential tools for scientific discovery in protein science. Resources are maintained at https://github.com/Yijia-Xiao/Protein-LLM-Survey.

Yijia Xiao
Wanjia Zhao
Junkai Zhang
Yiqiao Jin
Han Zhang
Zhicheng Ren
Renliang Sun
Haixin Wang
Guancheng Wan
Pan Lu
Xiao Luo
Yu Zhang
James Zou
Yizhou Sun
Wei Wang


Interpreting and Steering Protein Language Models through Sparse Autoencoders

Abstract: The rapid advancements in transformer-based language models have revolutionized natural language processing, yet understanding the internal mechanisms of these models remains a significant challenge. This paper explores the application of sparse autoencoders (SAE) to interpret the internal representations of protein language models, specifically focusing on the ESM-2 8M parameter model. By performing a statistical analysis on each latent component's relevance to distinct protein annotations, we identify potential interpretations linked to various protein characteristics, including transmembrane regions, binding sites, and specialized motifs. We then leverage these insights to guide sequence generation, shortlisting the relevant latent components that can steer the model towards desired targets such as zinc finger domains. This work contributes to the emerging field of mechanistic interpretability in biological sequence models, offering new perspectives on model steering for sequence design.

Edith Natalia Villegas Garcia
Alessio Ansuini


Uncertainty-Aware Adaptation of Large Language Models for Protein-Protein Interaction Analysis

Abstract: Identification of protein-protein interactions (PPIs) helps derive cellular mechanistic understanding, particularly in the context of complex conditions such as neurodegenerative disorders, metabolic syndromes, and cancer. Large Language Models (LLMs) have demonstrated remarkable potential in predicting protein structures and interactions via automated mining of vast biomedical literature; yet their inherent uncertainty remains a key challenge for deriving reproducible findings, critical for biomedical applications. In this study, we present an uncertainty-aware adaptation of LLMs for PPI analysis, leveraging fine-tuned LLaMA-3 and BioMedGPT models. To enhance prediction reliability, we integrate LoRA ensembles and Bayesian LoRA models for uncertainty quantification (UQ), ensuring confidence-calibrated insights into protein behavior. Our approach achieves competitive performance in PPI identification across diverse disease contexts while addressing model uncertainty, thereby enhancing trustworthiness and reproducibility in computational biology. These findings underscore the potential of uncertainty-aware LLM adaptation for advancing precision medicine and biomedical research.

Sanket Jantre
Tianle Wang
Gilchan Park
Kriti Chopra
Nicholas Jeon
Xiaoning Qian
Nathan M. Urban
Byung-Jun Yoon

Annual International Conference of the IEEE Engineering in Medicine and Biology Society


PyMOLfold: Interactive Protein and Ligand Structure Prediction in PyMOL

Abstract: PyMOLfold is a flexible and open-source plugin designed to seamlessly integrate AI-based protein structure prediction and visualization within the widely used PyMOL molecular graphics system. By leveraging state-of-the-art protein folding models such as ESM3, Boltz-1, and Chai-1, PyMOLfold allows researchers to directly predict protein tertiary structures from amino acid sequences without requiring external tools or complex workflows. Furthermore, with certain models, users can provide a SMILES string of a ligand and have the small molecule placed in the protein structure. This unique capability bridges the gap between computational folding and structural visualization, enabling users to input a primary sequence, perform a folding prediction, and immediately explore the resulting 3D structure within the same intuitive platform.

Colby T. Ford
Samee Ullah
Dinler Amaral Antunes
Tarsis Gesteira Ferreira


Exploring Large Protein Language Models in Constrained Evaluation Scenarios within the FLIP Benchmark

Abstract: In this study, we expand upon the FLIP benchmark-designed for evaluating protein fitness prediction models in small, specialized prediction tasks-by assessing the performance of state-of-the-art large protein language models, including ESM-2 and SaProt on the FLIP dataset. Unlike larger, more diverse benchmarks such as ProteinGym, which cover a broad spectrum of tasks, FLIP focuses on constrained settings where data availability is limited. This makes it an ideal framework to evaluate model performance in scenarios with scarce task-specific data. We investigate whether recent advances in protein language models lead to significant improvements in such settings. Our findings provide valuable insights into the performance of large-scale models in specialized protein prediction tasks.

Manuel F. Mollon
Joaquin Gonzalez-Rodriguez
Alicia Lozano-Diez
Daniel Ramos
Doroteo T. Toledano