Learning the Language of Protein Structure

Abstract: Representation learning and \emph{de novo} generation of proteins are pivotal computational biology tasks. Whilst natural language processing (NLP) techniques have proven highly effective for protein sequence modelling, structure modelling presents a complex challenge, primarily due to its continuous and three-dimensional nature. Motivated by this discrepancy, we introduce an approach using a vector-quantized autoencoder that effectively tokenizes protein structures into discrete representations. This method transforms the continuous, complex space of protein structures into a manageable, discrete format with a codebook ranging from 4096 to 64000 tokens, achieving high-fidelity reconstructions with backbone root mean square deviations (RMSD) of approximately 1-5 Å. To demonstrate the efficacy of our learned representations, we show that a simple GPT model trained on our codebooks can generate novel, diverse, and designable protein structures. Our approach not only provides representations of protein structure, but also mitigates the challenges of disparate modal representations and sets a foundation for seamless, multi-modal integration, enhancing the capabilities of computational methods in protein design.

Benoit Gaujac
Jérémie Donà
Liviu Copoiu
Timothy Atkinson
Thomas Pierrot
Thomas D. Barrett


Babysit A Language Model From Scratch: Interactive Language Learning by Trials and Demonstrations

Abstract: Humans are efficient language learners and inherently social creatures. Our language development is largely shaped by our social interactions, for example, the demonstration and feedback from caregivers. Contrary to human language learning, recent advancements in large language models have primarily adopted a non-interactive training paradigm, and refined pre-trained models through feedback afterward. In this work, we explore how corrective feedback from interactions influences neural language acquisition from scratch through systematically controlled experiments, assessing whether it contributes to word learning efficiency in language models. We introduce a trial-and-demonstration (TnD) learning framework that incorporates three distinct components: student trials, teacher demonstrations, and a reward conditioned on language competence at various developmental stages. Our experiments reveal that the TnD approach accelerates word acquisition for student models of equal and smaller numbers of parameters, and we highlight the significance of both trials and demonstrations. We further show that the teacher's choices of words influence students' word-specific learning efficiency, and a practice-makes-perfect effect is evident by a strong correlation between the frequency of words in trials and their respective learning curves. Our findings suggest that interactive language learning, with teacher demonstrations and active trials, can facilitate efficient word learning in language models.

North American Chapter of the Association for Computational Linguistics


Identifying the minimal sets of distance restraints for FRET-assisted protein structural modeling

Abstract: Proteins naturally occur in crowded cellular environments and interact with other proteins, nucleic acids, and organelles. Since most previous experimental protein structure determination techniques require that proteins occur in idealized, non-physiological environments, the effects of realistic cellular environments on protein structure are largely unexplored. Recently, Förster resonance energy transfer (FRET) has been shown to be an effective experimental method for investigating protein structure in vivo. Inter-residue distances measured in vivo can be incorporated as restraints in molecular dynamics (MD) simulations to model protein structural dynamics in vivo. Since most FRET studies only obtain inter-residue separations for a small number of amino acid pairs, it is important to determine the minimum number of restraints in the MD simulations that are required to achieve a given root-mean-square deviation (RMSD) from the experimental structural ensemble. Further, what is the optimal method for selecting these inter-residue restraints? Here, we implement several methods for selecting the most important FRET pairs and determine the number of pairs $N_{r}$ that are needed to induce conformational changes in proteins between two experimentally determined structures. We find that enforcing only a small fraction of restraints, $N_{r}/N \lesssim 0.08$, where $N$ is the number of amino acids, can induce the conformational changes. These results establish the efficacy of FRET-assisted MD simulations for atomic scale structural modeling of proteins in vivo.

Zhuoyi Liu
Alex T. Grigas
Jacob Sumner
Edward Knab
Caitlin M. Davis
Corey S. O'Hern


Fine-tuning Protein Language Models with Deep Mutational Scanning improves Variant Effect Prediction

Abstract: Protein Language Models (PLMs) have emerged as performant and scalable tools for predicting the functional impact and clinical significance of protein-coding variants, but they still lag experimental accuracy. Here, we present a novel fine-tuning approach to improve the performance of PLMs with experimental maps of variant effects from Deep Mutational Scanning (DMS) assays using a Normalised Log-odds Ratio (NLR) head. We find consistent improvements in a held-out protein test set, and on independent DMS and clinical variant annotation benchmarks from ProteinGym and ClinVar. These findings demonstrate that DMS is a promising source of sequence diversity and supervised training data for improving the performance of PLMs for variant effect prediction.

Aleix Lafita
Ferran Gonzalez
Mahmoud Hossam
Paul Smyth
Jacob Deasy
Ari Allyn-Feuer
Daniel Seaton
Stephen Young


Protein binding affinity prediction under multiple substitutions applying eGNNs on Residue and Atomic graphs combined with Language model information: eGRAL

Abstract: Protein-protein interactions (PPIs) play a crucial role in numerous biological processes. Developing methods that predict binding affinity changes under substitution mutations is fundamental for modelling and re-engineering biological systems. Deep learning is increasingly recognized as a powerful tool capable of bridging the gap between in-silico predictions and in-vitro observations. With this contribution, we propose eGRAL, a novel SE(3) equivariant graph neural network (eGNN) architecture designed for predicting binding affinity changes from multiple amino acid substitutions in protein complexes. eGRAL leverages residue, atomic and evolutionary scales, thanks to features extracted from protein large language models. To address the limited availability of large-scale affinity assays with structural information, we generate a simulated dataset comprising approximately 500,000 data points. Our model is pre-trained on this dataset, then fine-tuned and tested on experimental data.

Arturo Fiorellini-Bernardis
Sebastien Boyer
Christoph Brunken
Bakary Diallo
Karim Beguir
Nicolas Lopez-Carranza
Oliver Bent


Detection of circular permutations by Protein Language Models

Abstract: Protein circular permutations are crucial for understanding protein evolution and functionality. Traditional detection methods, sequence-based or structure-based, struggle with accuracy and computational efficiency, the latter also limited by treating proteins as rigid bodies. The plmCP method, utilizing a protein language model, not only speeds up the detection process but also enhances the accuracy of identifying circular permutations, contributing significantly to protein research and engineering by acknowledging structural flexibility.

Computational and Structural Biotechnology Journal


Simple, Efficient and Scalable Structure-aware Adapter Boosts Protein Language Models

Abstract: Fine-tuning Pre-trained protein language models (PLMs) has emerged as a prominent strategy for enhancing downstream prediction tasks, often outperforming traditional supervised learning approaches. As a widely applied powerful technique in natural language processing, employing Parameter-Efficient Fine-Tuning techniques could potentially enhance the performance of PLMs. However, the direct transfer to life science tasks is non-trivial due to the different training strategies and data forms. To address this gap, we introduce SES-Adapter, a simple, efficient, and scalable adapter method for enhancing the representation learning of PLMs. SES-Adapter incorporates PLM embeddings with structural sequence embeddings to create structure-aware representations. We show that the proposed method is compatible with different PLM architectures and across diverse tasks. Extensive evaluations are conducted on 2 types of folding structures with notable quality differences, 9 state-of-the-art baselines, and 9 benchmark datasets across distinct downstream tasks. Results show that compared to vanilla PLMs, SES-Adapter improves downstream task performance by a maximum of 11% and an average of 3%, with significantly accelerated training speed by a maximum of 1034% and an average of 362%, the convergence rate is also improved by approximately 2 times. Moreover, positive optimization is observed even with low-quality predicted structures. The source code for SES-Adapter is available at https://github.com/tyang816/SES-Adapter.

Yang Tan
Mingchen Li
Bingxin Zhou
Bozitao Zhong
Lirong Zheng
Pan Tan
Ziyi Zhou
Huiqun Yu
Guisheng Fan
Liang Hong

Journal of Chemical Information and Modeling


ScaleFold: Reducing AlphaFold Initial Training Time to 10 Hours

Abstract: AlphaFold2 has been hailed as a breakthrough in protein folding. It can rapidly predict protein structures with lab-grade accuracy. However, its implementation does not include the necessary training code. OpenFold is the first trainable public reimplementation of AlphaFold. AlphaFold training procedure is prohibitively time-consuming, and gets diminishing benefits from scaling to more compute resources. In this work, we conducted a comprehensive analysis on the AlphaFold training procedure based on Openfold, identified that inefficient communications and overhead-dominated computations were the key factors that prevented the AlphaFold training from effective scaling. We introduced ScaleFold, a systematic training method that incorporated optimizations specifically for these factors. ScaleFold successfully scaled the AlphaFold training to 2080 NVIDIA H100 GPUs with high resource utilization. In the MLPerf HPC v3.0 benchmark, ScaleFold finished the OpenFold benchmark in 7.51 minutes, shown over $6\times$ speedup than the baseline. For training the AlphaFold model from scratch, ScaleFold completed the pretraining in 10 hours, a significant improvement over the seven days required by the original AlphaFold pretraining baseline.

Feiwen Zhu
Arkadiusz Nowaczynski
Rundong Li
Jie Xin
Yifei Song
Michal Marcinkiewicz
Sukru Burc Eryilmaz
Jun Yang
Michael Andersch


HelixFold-Multimer: Elevating Protein Complex Structure Prediction to New Heights

Abstract: While monomer protein structure prediction tools boast impressive accuracy, the prediction of protein complex structures remains a daunting challenge in the field. This challenge is particularly pronounced in scenarios involving complexes with protein chains from different species, such as antigen-antibody interactions, where accuracy often falls short. Limited by the accuracy of complex prediction, tasks based on precise protein-protein interaction analysis also face obstacles. In this report, we highlight the ongoing advancements of our protein complex structure prediction model, HelixFold-Multimer, underscoring its enhanced performance. HelixFold-Multimer provides precise predictions for diverse protein complex structures, especially in therapeutic protein interactions. Notably, HelixFold-Multimer achieves remarkable success in antigen-antibody and peptide-protein structure prediction, greatly surpassing AlphaFold 3. HelixFold-Multimer is now available for public use on the PaddleHelix platform, offering both a general version and an antigen-antibody version. Researchers can conveniently access and utilize this service for their development needs.

Xiaomin Fang
Jie Gao
Jing Hu
Lihang Liu
Yang Xue
Xiaonan Zhang
Kunrui Zhu


PRODIS -- a speech database and a phoneme-based language model for the study of predictability effects in Polish

Abstract: We present a speech database and a phoneme-level language model of Polish. The database and model are designed for the analysis of prosodic and discourse factors and their impact on acoustic parameters in interaction with predictability effects. The database is also the first large, publicly available Polish speech corpus of excellent acoustic quality that can be used for phonetic analysis and training of multi-speaker speech technology systems. The speech in the database is processed in a pipeline that achieves a 90% degree of automation. It incorporates state-of-the-art, freely available tools enabling database expansion or adaptation to additional languages.

Zofia Malisz
Jan Foremski
Małgorzata Kul

International Conference on Language Resources and Evaluation


Auxiliary task demands mask the capabilities of smaller language models

Abstract: Developmental psychologists have argued about when cognitive capacities such as language understanding or theory of mind emerge. These debates often hinge on the concept of "task demands" -- the auxiliary challenges associated with performing a particular evaluation -- that may mask the child's underlying ability. The same issues arise when measuring the capacities of language models (LMs): performance on a task is a function of the model's underlying knowledge, combined with the model's ability to interpret and perform the task given its available resources. Here, we show that for analogical reasoning, reflective reasoning, word prediction, and grammaticality judgments, evaluation methods with greater task demands yield lower performance than evaluations with reduced demands. This "demand gap" is most pronounced for models with fewer parameters and less training data. Our results illustrate that LM performance should not be interpreted as a direct indication of intelligence (or lack thereof), but as a reflection of capacities seen through the lens of researchers' design choices.


ProLLM: Protein Chain-of-Thoughts Enhanced LLM for Protein-Protein Interaction Prediction

Abstract: The prediction of protein-protein interactions (PPIs) is crucial for understanding biological functions and diseases. Previous machine learning approaches to PPI prediction mainly focus on direct physical interactions, ignoring the broader context of nonphysical connections through intermediate proteins, thus limiting their effectiveness. The emergence of Large Language Models (LLMs) provides a new opportunity for addressing this complex biological challenge. By transforming structured data into natural language prompts, we can map the relationships between proteins into texts. This approach allows LLMs to identify indirect connections between proteins, tracing the path from upstream to downstream. Therefore, we propose a novel framework ProLLM that employs an LLM tailored for PPI for the first time. Specifically, we propose Protein Chain of Thought (ProCoT), which replicates the biological mechanism of signaling pathways as natural language prompts. ProCoT considers a signaling pathway as a protein reasoning process, which starts from upstream proteins and passes through several intermediate proteins to transmit biological signals to downstream proteins. Thus, we can use ProCoT to predict the interaction between upstream proteins and downstream proteins. The training of ProLLM employs the ProCoT format, which enhances the model's understanding of complex biological problems. In addition to ProCoT, this paper also contributes to the exploration of embedding replacement of protein sites in natural language prompts, and instruction fine-tuning in protein knowledge datasets. We demonstrate the efficacy of ProLLM through rigorous validation against benchmark datasets, showing significant improvement over existing methods in terms of prediction accuracy and generalizability. The code is available at: https://github.com/MingyuJ666/ProLLM.

Mingyu Jin
Haochen Xue
Zhenting Wang
Boming Kang
Ruosong Ye
Kaixiong Zhou
Mengnan Du
Yongfeng Zhang


IDP-Bert: Predicting Properties of Intrinsically Disordered Proteins (IDP) Using Large Language Models

Abstract: Intrinsically Disordered Proteins (IDPs) constitute a large and structure-less class of proteins with significant functions. The existence of IDPs challenges the conventional notion that the biological functions of proteins rely on their three-dimensional structures. Despite lacking well-defined spatial arrangements, they exhibit diverse biological functions, influencing cellular processes and shedding light on the disease mechanisms. However, it is expensive to run experiments or simulations to characterize this class of proteins. Consequently, we designed an ML model that relies solely on amino acid sequences. In this study, we introduce IDP-Bert model, a deep-learning architecture leveraging Transformers and Protein Language Models (PLMs) to map sequences directly to IDPs properties. Our experiments demonstrate accurate predictions of IDPs properties, including Radius of Gyration, end-to-end Decorrelation Time, and Heat Capacity.

Parisa Mollaei
Danush Sadasivam
Chakradhar Guntuboina
Amir Barati Farimani


Are Compressed Language Models Less Subgroup Robust?

Abstract: To reduce the inference cost of large language models, model compression is increasingly used to create smaller scalable models. However, little is known about their robustness to minority subgroups defined by the labels and attributes of a dataset. In this paper, we investigate the effects of 18 different compression methods and settings on the subgroup robustness of BERT language models. We show that worst-group performance does not depend on model size alone, but also on the compression method used. Additionally, we find that model compression does not always worsen the performance on minority subgroups. Altogether, our analysis serves to further research into the subgroup robustness of model compression.

Leonidas Gee
Andrea Zugarini
Novi Quadrianto

Conference on Empirical Methods in Natural Language Processing


Emergent World Models and Latent Variable Estimation in Chess-Playing Language Models

Abstract: Language models have shown unprecedented capabilities, sparking debate over the source of their performance. Is it merely the outcome of learning syntactic patterns and surface level statistics, or do they extract semantics and a world model from the text? Prior work by Li et al. investigated this by training a GPT model on synthetic, randomly generated Othello games and found that the model learned an internal representation of the board state. We extend this work into the more complex domain of chess, training on real games and investigating our model's internal representations using linear probes and contrastive activations. The model is given no a priori knowledge of the game and is solely trained on next character prediction, yet we find evidence of internal representations of board state. We validate these internal representations by using them to make interventions on the model's activations and edit its internal board state. Unlike Li et al's prior synthetic dataset approach, our analysis finds that the model also learns to estimate latent variables like player skill to better predict the next character. We derive a player skill vector and add it to the model, improving the model's win rate by up to 2.6 times.


Clinical information extraction for Low-resource languages with Few-shot learning using Pre-trained language models and Prompting

Abstract: Automatic extraction of medical information from clinical documents poses several challenges: high costs of required clinical expertise, limited interpretability of model predictions, restricted computational resources and privacy regulations. Recent advances in domain-adaptation and prompting methods showed promising results with minimal training data using lightweight masked language models, which are suited for well-established interpretability methods. We are first to present a systematic evaluation of these methods in a low-resource setting, by performing multi-class section classification on German doctor's letters. We conduct extensive class-wise evaluations supported by Shapley values, to validate the quality of our small training data set and to ensure the interpretability of model predictions. We demonstrate that a lightweight, domain-adapted pretrained model, prompted with just 20 shots, outperforms a traditional classification model by 30.5% accuracy. Our results serve as a process-oriented guideline for clinical information extraction projects working with low-resource.

Phillip Richter-Pechanski
Philipp Wiesenbach
Dominic M. Schwab
Christina Kiriakou
Nicolas Geis
Christoph Dieterich
Anette Frank


Document Author Classification Using Parsed Language Structure

Abstract: Over the years there has been ongoing interest in detecting authorship of a text based on statistical properties of the text, such as by using occurrence rates of noncontextual words. In previous work, these techniques have been used, for example, to determine authorship of all of \emph{The Federalist Papers}. Such methods may be useful in more modern times to detect fake or AI authorship. Progress in statistical natural language parsers introduces the possibility of using grammatical structure to detect authorship. In this paper we explore a new possibility for detecting authorship using grammatical structural information extracted using a statistical natural language parser. This paper provides a proof of concept, testing author classification based on grammatical structure on a set of "proof texts," The Federalist Papers and Sanditon which have been as test cases in previous authorship detection studies. Several features extracted from the statistical natural language parser were explored: all subtrees of some depth from any level; rooted subtrees of some depth, part of speech, and part of speech by level in the parse tree. It was found to be helpful to project the features into a lower dimensional space. Statistical experiments on these documents demonstrate that information from a statistical parser can, in fact, assist in distinguishing authors.

International Journal on Natural Language Computing


Pragmatic Competence Evaluation of Large Language Models for the Korean Language

Abstract: Benchmarks play a significant role in the current evaluation of Large Language Models (LLMs), yet they often overlook the models' abilities to capture the nuances of human language, primarily focusing on evaluating embedded knowledge and technical skills. To address this gap, our study evaluates how well LLMs understand context-dependent expressions from a pragmatic standpoint, specifically in Korean. We use both Multiple-Choice Questions (MCQs) for automatic evaluation and Open-Ended Questions (OEQs) assessed by human experts. Our results show that GPT-4 leads with scores of 81.11 in MCQs and 85.69 in OEQs, closely followed by HyperCLOVA X. Additionally, while few-shot learning generally improves performance, Chain-of-Thought (CoT) prompting tends to encourage literal interpretations, which may limit effective pragmatic inference. Our findings highlight the need for LLMs to better understand and generate language that reflects human communicative norms.

Dojun Park
Jiwoo Lee
Hyeyun Jeong
Seohyun Park
Sungeun Lee

Pacific Asia Conference on Language, Information and Computation


Language Evolution with Deep Learning

Abstract: Computational modeling plays an essential role in the study of language emergence. It aims to simulate the conditions and learning processes that could trigger the emergence of a structured language within a simulated controlled environment. Several methods have been used to investigate the origin of our language, including agent-based systems, Bayesian agents, genetic algorithms, and rule-based systems. This chapter explores another class of computational models that have recently revolutionized the field of machine learning: deep learning models. The chapter introduces the basic concepts of deep and reinforcement learning methods and summarizes their helpfulness for simulating language emergence. It also discusses the key findings, limitations, and recent attempts to build realistic simulations. This chapter targets linguists and cognitive scientists seeking an introduction to deep learning as a tool to investigate language evolution.

Mathieu Rita
Paul Michel
Rahma Chaabouni
Olivier Pietquin
Emmanuel Dupoux
Florian Strub


On Recovering Higher-order Interactions from Protein Language Models

Abstract: Protein language models leverage evolutionary information to perform state-of-the-art 3D structure and zero-shot variant prediction. Yet, extracting and explaining all the mutational interactions that govern model predictions remains difficult as it requires querying the entire amino acid space for $n$ sites using $20^n$ sequences, which is computationally expensive even for moderate values of $n$ (e.g., $n\sim10$). Although approaches to lower the sample complexity exist, they often limit the interpretability of the model to just single and pairwise interactions. Recently, computationally scalable algorithms relying on the assumption of sparsity in the Fourier domain have emerged to learn interactions from experimental data. However, extracting interactions from language models poses unique challenges: it's unclear if sparsity is always present or if it is the only metric needed to assess the utility of Fourier algorithms. Herein, we develop a framework to do a systematic Fourier analysis of the protein language model ESM2 applied on three proteins-green fluorescent protein (GFP), tumor protein P53 (TP53), and G domain B1 (GB1)-across various sites for 228 experiments. We demonstrate that ESM2 is dominated by three regions in the sparsity-ruggedness plane, two of which are better suited for sparse Fourier transforms. Validations on two sample proteins demonstrate recovery of all interactions with $R^2=0.72$ in the more sparse region and $R^2=0.66$ in the more dense region, using only 7 million out of $20^{10}\sim10^{13}$ ESM2 samples, reducing the computational time by a staggering factor of 15,000. All codes and data are available on our GitHub repository https://github.com/amirgroup-codes/InteractionRecovery.


Diffusion on language model encodings for protein sequence generation

Abstract: Protein sequence design has seen significant advances through discrete diffusion and autoregressive approaches, yet the potential of continuous diffusion remains underexplored. Here, we present DiMA, a latent diffusion framework that operates on protein language model representations. Through systematic exploration of architectural choices and diffusion components, we develop a robust methodology that generalizes across multiple protein encoders ranging from 8M to 3B parameters. We demonstrate that our framework achieves consistently high performance across sequence-only (ESM-2, ESMc), dual-decodable (CHEAP), and multimodal (SaProt) representations using the same architecture and training approach. We extensively evaluate existing methods alongside DiMA using multiple metrics across two protein modalities, covering quality, diversity, novelty, and distribution matching of generated proteins. DiMA consistently produces novel, high-quality and diverse protein sequences and achieves strong results compared to baselines such as autoregressive, discrete diffusion and flow matching language models. The model demonstrates versatile functionality, supporting conditional generation tasks including protein family-generation, motif scaffolding and infilling, and fold-specific sequence design. This work provides a universal continuous diffusion framework for protein sequence generation, offering both architectural insights and practical applicability across various protein design scenarios. Code is released at \href{https://github.com/MeshchaninovViacheslav/DiMA}{GitHub}.

Viacheslav Meshchaninov
Pavel Strashnov
Andrey Shevtsov
Fedor Nikolaev
Nikita Ivanisenko
Olga Kardymon
Dmitry Vetrov

International Conference on Machine Learning


ESM All-Atom: Multi-scale Protein Language Model for Unified Molecular Modeling

Abstract: Protein language models have demonstrated significant potential in the field of protein engineering. However, current protein language models primarily operate at the residue scale, which limits their ability to provide information at the atom level. This limitation prevents us from fully exploiting the capabilities of protein language models for applications involving both proteins and small molecules. In this paper, we propose ESM-AA (ESM All-Atom), a novel approach that enables atom-scale and residue-scale unified molecular modeling. ESM-AA achieves this by pre-training on multi-scale code-switch protein sequences and utilizing a multi-scale position encoding to capture relationships among residues and atoms. Experimental results indicate that ESM-AA surpasses previous methods in protein-molecule tasks, demonstrating the full utilization of protein language models. Further investigations reveal that through unified molecular modeling, ESM-AA not only gains molecular knowledge but also retains its understanding of proteins. The source codes of ESM-AA are publicly released at https://github.com/zhengkangjie/ESM-AA.

Kangjie Zheng
Siyu Long
Tianyu Lu
Junwei Yang
Xinyu Dai
Ming Zhang
Zaiqing Nie
Wei-Ying Ma
Hao Zhou


A Protein Structure Prediction Approach Leveraging Transformer and CNN Integration

Abstract: Proteins are essential for life, and their structure determines their function. The protein secondary structure is formed by the folding of the protein primary structure, and the protein tertiary structure is formed by the bending and folding of the secondary structure. Therefore, the study of protein secondary structure is very helpful to the overall understanding of protein structure. Although the accuracy of protein secondary structure prediction has continuously improved with the development of machine learning and deep learning, progress in the field of protein structure prediction, unfortunately, remains insufficient to meet the large demand for protein information. Therefore, based on the advantages of deep learning-based methods in feature extraction and learning ability, this paper adopts a two-dimensional fusion deep neural network model, DstruCCN, which uses Convolutional Neural Networks (CCN) and a supervised Transformer protein language model for single-sequence protein structure prediction. The training features of the two are combined to predict the protein Transformer binding site matrix, and then the three-dimensional structure is reconstructed using energy minimization.

Yanlin Zhou
Kai Tan
Xinyu Shen
Zheng He
Haotian Zheng


Protein Multimer Structure Prediction via Prompt Learning

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

Ziqi Gao
Xiangguo Sun
Zijing Liu
Yu Li
Hong Cheng
Jia Li

International Conference on Learning Representations


ProtLLM: An Interleaved Protein-Language LLM with Protein-as-Word Pre-Training

Abstract: We propose ProtLLM, a versatile cross-modal large language model (LLM) for both protein-centric and protein-language tasks. ProtLLM features a unique dynamic protein mounting mechanism, enabling it to handle complex inputs where the natural language text is interspersed with an arbitrary number of proteins. Besides, we propose the protein-as-word language modeling approach to train ProtLLM. By developing a specialized protein vocabulary, we equip the model with the capability to predict not just natural language but also proteins from a vast pool of candidates. Additionally, we construct a large-scale interleaved protein-text dataset, named InterPT, for pre-training. This dataset comprehensively encompasses both (1) structured data sources like protein annotations and (2) unstructured data sources like biological research papers, thereby endowing ProtLLM with crucial knowledge for understanding proteins. We evaluate ProtLLM on classic supervised protein-centric tasks and explore its novel protein-language applications. Experimental results demonstrate that ProtLLM not only achieves superior performance against protein-specialized baselines on protein-centric tasks but also induces zero-shot and in-context learning capabilities on protein-language tasks.

Le Zhuo
Zewen Chi
Minghao Xu
Heyan Huang
Heqi Zheng
Conghui He
Xian-Ling Mao
Wentao Zhang

Annual Meeting of the Association for Computational Linguistics


Diffusion Language Models Are Versatile Protein Learners

Abstract: This paper introduces diffusion protein language model (DPLM), a versatile protein language model that demonstrates strong generative and predictive capabilities for protein sequences. We first pre-train scalable DPLMs from evolutionary-scale protein sequences within a generative self-supervised discrete diffusion probabilistic framework, which generalizes language modeling for proteins in a principled way. After pre-training, DPLM exhibits the ability to generate structurally plausible, novel, and diverse protein sequences for unconditional generation. We further demonstrate the proposed diffusion generative pre-training makes DPLM possess a better understanding of proteins, making it a superior representation learner, which can be fine-tuned for various predictive tasks, comparing favorably to ESM2 (Lin et al., 2022). Moreover, DPLM can be tailored for various needs, which showcases its prowess of conditional generation in several ways: (1) conditioning on partial peptide sequences, e.g., generating scaffolds for functional motifs with high success rate; (2) incorporating other modalities as conditioner, e.g., structure-conditioned generation for inverse folding; and (3) steering sequence generation towards desired properties, e.g., satisfying specified secondary structures, through a plug-and-play classifier guidance. Code is released at \url{https://github.com/bytedance/dplm}.

Xinyou Wang
Zaixiang Zheng
Fei Ye
Dongyu Xue
Shujian Huang
Quanquan Gu


ProLLaMA: A Protein Large Language Model for Multi-Task Protein Language Processing

Abstract: Recent advances in Protein Language Models (PLMs) have transformed protein engineering, yet unlike their counterparts in Natural Language Processing (NLP), current PLMs exhibit a fundamental limitation: they excel in either Protein Language Understanding (PLU) or Protein Language Generation (PLG), but rarely both. This fragmentation hinders progress in protein engineering. To bridge this gap, we introduce ProLLaMA, a multitask protein language model enhanced by the Evolutionary Protein Generation Framework (EPGF). We construct a comprehensive instruction dataset containing approximately 13 million samples with over 11,000 superfamily annotations to facilitate better modeling of sequence-function landscapes. We leverage a two-stage training approach to develop ProLLaMA, a multitask LLM with protein domain expertise. Our EPGF addresses the mismatch between statistic language modeling and biological constraints through three innovations: a multi-dimensional interpretable scorer, hierarchical efficient decoding, and a probabilistic-biophysical joint selection mechanism. Extensive experiments demonstrate that ProLLaMA excels in both unconditional and controllable protein generation tasks, achieving superior structural quality metrics compared to existing PLMs. Additionally, ProLLaMA demonstrates strong understanding capabilities with a 67.1% exact match rate in superfamily prediction. EPGF significantly enhances the biological viability of generated sequences, as evidenced by improved biophysical scores (+4.3%) and structural metrics (+14.5%). The project is available at https://github.com/PKU-YuanGroup/ProLLaMA.

Liuzhenghao Lv
Zongying Lin
Hao Li
Yuyang Liu
Jiaxi Cui
Calvin Yu-Chian Chen
Li Yuan
Yonghong Tian

IEEE Transactions on Artificial Intelligence


How Important Is Tokenization in French Medical Masked Language Models?

Abstract: Subword tokenization has become the prevailing standard in the field of natural language processing (NLP) over recent years, primarily due to the widespread utilization of pre-trained language models. This shift began with Byte-Pair Encoding (BPE) and was later followed by the adoption of SentencePiece and WordPiece. While subword tokenization consistently outperforms character and word-level tokenization, the precise factors contributing to its success remain unclear. Key aspects such as the optimal segmentation granularity for diverse tasks and languages, the influence of data sources on tokenizers, and the role of morphological information in Indo-European languages remain insufficiently explored. This is particularly pertinent for biomedical terminology, characterized by specific rules governing morpheme combinations. Despite the agglutinative nature of biomedical terminology, existing language models do not explicitly incorporate this knowledge, leading to inconsistent tokenization strategies for common terms. In this paper, we seek to delve into the complexities of subword tokenization in French biomedical domain across a variety of NLP tasks and pinpoint areas where further enhancements can be made. We analyze classical tokenization algorithms, including BPE and SentencePiece, and introduce an original tokenization strategy that integrates morpheme-enriched word segmentation into existing tokenization methods.

Yanis Labrak
Adrien Bazoge
Beatrice Daille
Mickael Rouvier
Richard Dufour


Analysing The Impact of Sequence Composition on Language Model Pre-Training

Abstract: Most language model pre-training frameworks concatenate multiple documents into fixed-length sequences and use causal masking to compute the likelihood of each token given its context; this strategy is widely adopted due to its simplicity and efficiency. However, to this day, the influence of the pre-training sequence composition strategy on the generalisation properties of the model remains under-explored. In this work, we find that applying causal masking can lead to the inclusion of distracting information from previous documents during pre-training, which negatively impacts the performance of the models on language modelling and downstream tasks. In intra-document causal masking, the likelihood of each token is only conditioned on the previous tokens in the same document, eliminating potential distracting information from previous documents and significantly improving performance. Furthermore, we find that concatenating related documents can reduce some potential distractions during pre-training, and our proposed efficient retrieval-based sequence construction method, BM25Chunk, can improve in-context learning (+11.6\%), knowledge memorisation (+9.8\%), and context utilisation (+7.2\%) abilities of language models without sacrificing efficiency.

Yu Zhao
Yuanbin Qu
Konrad Staniszewski
Szymon Tworkowski
Wei Liu
Piotr Miłoś
Yuxiang Wu
Pasquale Minervini


TEXT2AFFORD: Probing Object Affordance Prediction abilities of Language Models solely from Text

Abstract: We investigate the knowledge of object affordances in pre-trained language models (LMs) and pre-trained Vision-Language models (VLMs). A growing body of literature shows that PTLMs fail inconsistently and non-intuitively, demonstrating a lack of reasoning and grounding. To take a first step toward quantifying the effect of grounding (or lack thereof), we curate a novel and comprehensive dataset of object affordances -- Text2Afford, characterized by 15 affordance classes. Unlike affordance datasets collected in vision and language domains, we annotate in-the-wild sentences with objects and affordances. Experimental results reveal that PTLMs exhibit limited reasoning abilities when it comes to uncommon object affordances. We also observe that pre-trained VLMs do not necessarily capture object affordances effectively. Through few-shot fine-tuning, we demonstrate improvement in affordance knowledge in PTLMs and VLMs. Our research contributes a novel dataset for language grounding tasks, and presents insights into LM capabilities, advancing the understanding of object affordances. Codes and data are available at https://github.com/sayantan11995/Text2Afford

Sayantan Adak
Daivik Agrawal
Animesh Mukherjee
Somak Aditya

Conference on Computational Natural Language Learning


Exploring the Frontier of Vision-Language Models: A Survey of Current Methodologies and Future Directions

Abstract: The advent of Large Language Models (LLMs) has significantly reshaped the trajectory of the AI revolution. Nevertheless, these LLMs exhibit a notable limitation, as they are primarily adept at processing textual information. To address this constraint, researchers have endeavored to integrate visual capabilities with LLMs, resulting in the emergence of Vision-Language Models (VLMs). These advanced models are instrumental in tackling more intricate tasks such as image captioning and visual question answering. In our comprehensive survey paper, we delve into the key advancements within the realm of VLMs. Our classification organizes VLMs into three distinct categories: models dedicated to vision-language understanding, models that process multimodal inputs to generate unimodal (textual) outputs and models that both accept and produce multimodal inputs and outputs.This classification is based on their respective capabilities and functionalities in processing and generating various modalities of data.We meticulously dissect each model, offering an extensive analysis of its foundational architecture, training data sources, as well as its strengths and limitations wherever possible, providing readers with a comprehensive understanding of its essential components. We also analyzed the performance of VLMs in various benchmark datasets. By doing so, we aim to offer a nuanced understanding of the diverse landscape of VLMs. Additionally, we underscore potential avenues for future research in this dynamic domain, anticipating further breakthroughs and advancements.

Akash Ghosh
Arkadeep Acharya
Sriparna Saha
Vinija Jain
Aman Chadha


Learning From Failure: Integrating Negative Examples when Fine-tuning Large Language Models as Agents

Abstract: Large language models (LLMs) have achieved success in acting as agents, which interact with environments through tools such as search engines. However, LLMs are optimized for language generation instead of tool use during training or alignment, limiting their effectiveness as agents. To resolve this problem, previous work has first collected interaction trajectories between LLMs and environments, using only trajectories that successfully finished the task to fine-tune smaller models, making fine-tuning data scarce and acquiring it both difficult and costly. Discarding failed trajectories also leads to significant wastage of data and resources and limits the possible optimization paths during fine-tuning. In this paper, we argue that unsuccessful trajectories offer valuable insights, and LLMs can learn from these trajectories through appropriate quality control and fine-tuning strategies. By simply adding a prefix or suffix that tells the model whether to generate a successful trajectory during training, we improve model performance by a large margin on mathematical reasoning, multi-hop question answering, and strategic question answering tasks. We further analyze the inference results and find that our method provides a better trade-off between valuable information and errors in unsuccessful trajectories. To our knowledge, we are the first to demonstrate the value of negative trajectories and their application in agent-tunning scenarios. Our findings offer guidance for developing better agent-tuning methods and low-resource data usage techniques.

Renxi Wang
Haonan Li
Xudong Han
Yixuan Zhang
Timothy Baldwin


Fast Vocabulary Transfer for Language Model Compression

Abstract: Real-world business applications require a trade-off between language model performance and size. We propose a new method for model compression that relies on vocabulary transfer. We evaluate the method on various vertical domains and downstream tasks. Our results indicate that vocabulary transfer can be effectively used in combination with other compression techniques, yielding a significant reduction in model size and inference time while marginally compromising on performance.

Leonidas Gee
Andrea Zugarini
Leonardo Rigutini
Paolo Torroni


ProtChatGPT: Towards Understanding Proteins with Large Language Models

Abstract: Protein research is crucial in various fundamental disciplines, but understanding their intricate structure-function relationships remains challenging. Recent Large Language Models (LLMs) have made significant strides in comprehending task-specific knowledge, suggesting the potential for ChatGPT-like systems specialized in protein to facilitate basic research. In this work, we introduce ProtChatGPT, which aims at learning and understanding protein structures via natural languages. ProtChatGPT enables users to upload proteins, ask questions, and engage in interactive conversations to produce comprehensive answers. The system comprises protein encoders, a Protein-Language Pertaining Transformer (PLP-former), a projection adapter, and an LLM. The protein first undergoes protein encoders and PLP-former to produce protein embeddings, which are then projected by the adapter to conform with the LLM. The LLM finally combines user questions with projected embeddings to generate informative answers. Experiments show that ProtChatGPT can produce promising responses to proteins and their corresponding questions. We hope that ProtChatGPT could form the basis for further exploration and application in protein research. Code and our pre-trained model will be publicly available.


Structured Language Generation Model: Loss Calibration and Formatted Decoding for Robust Structure Prediction and Knowledge Retrieval

Abstract: Modern generative pre-trained language models excel at open-ended text generation, yet continue to underperform on structure-related tasks such as NER, relation extraction, and semantic role labeling, especially when compared to encoder-only models of similar sizes. While this gap has been attributed to limited structure knowledge, we hypothesize this is also due to the missing connection between the model's internal representations of linguistic structure and the output space used during supervised fine-tuning. We propose the Structured Language Generation Model (SLGM), a model- and task-agnostic framework that reformulates structured prediction as a classification problem through three components: (1) reinforced input formatting with structural cues, (2) loss design, and (3) format-aware decoding that constrains generation to task-valid outputs. Across 5 tasks and 13 datasets, SLGM substantially improves structure prediction without relying on dataset-specific engineering or additional model parameters, strengthening alignment between the model's internal structure representation and output. It outperforms baseline fine-tuning on models of the same size, achieves comparable performance to much larger models when used with <1B parameter models, and acts as a zero-weight adapter that reproduces the benefits of dataset-specific fine-tuning in low-resource settings.

Minho Lee
Junghyun Min
Yerang Kim
Woochul Lee
Yeonsoo Lee


PSC-CPI: Multi-Scale Protein Sequence-Structure Contrasting for Efficient and Generalizable Compound-Protein Interaction Prediction

Abstract: Compound-Protein Interaction (CPI) prediction aims to predict the pattern and strength of compound-protein interactions for rational drug discovery. Existing deep learning-based methods utilize only the single modality of protein sequences or structures and lack the co-modeling of the joint distribution of the two modalities, which may lead to significant performance drops in complex real-world scenarios due to various factors, e.g., modality missing and domain shifting. More importantly, these methods only model protein sequences and structures at a single fixed scale, neglecting more fine-grained multi-scale information, such as those embedded in key protein fragments. In this paper, we propose a novel multi-scale Protein Sequence-structure Contrasting framework for CPI prediction (PSC-CPI), which captures the dependencies between protein sequences and structures through both intra-modality and cross-modality contrasting. We further apply length-variable protein augmentation to allow contrasting to be performed at different scales, from the amino acid level to the sequence level. Finally, in order to more fairly evaluate the model generalizability, we split the test data into four settings based on whether compounds and proteins have been observed during the training stage. Extensive experiments have shown that PSC-CPI generalizes well in all four settings, particularly in the more challenging ``Unseen-Both" setting, where neither compounds nor proteins have been observed during training. Furthermore, even when encountering a situation of modality missing, i.e., inference with only single-modality protein data, PSC-CPI still exhibits comparable or even better performance than previous approaches.

Lirong Wu
Yufei Huang
Cheng Tan
Zhangyang Gao
Bozhen Hu
Haitao Lin
Zicheng Liu
Stan Z. Li

AAAI Conference on Artificial Intelligence


Do Membership Inference Attacks Work on Large Language Models?

Abstract: Membership inference attacks (MIAs) attempt to predict whether a particular datapoint is a member of a target model's training data. Despite extensive research on traditional machine learning models, there has been limited work studying MIA on the pre-training data of large language models (LLMs). We perform a large-scale evaluation of MIAs over a suite of language models (LMs) trained on the Pile, ranging from 160M to 12B parameters. We find that MIAs barely outperform random guessing for most settings across varying LLM sizes and domains. Our further analyses reveal that this poor performance can be attributed to (1) the combination of a large dataset and few training iterations, and (2) an inherently fuzzy boundary between members and non-members. We identify specific settings where LLMs have been shown to be vulnerable to membership inference and show that the apparent success in such settings can be attributed to a distribution shift, such as when members and non-members are drawn from the seemingly identical domain but with different temporal ranges. We release our code and data as a unified benchmark package that includes all existing MIAs, supporting future work.

Michael Duan
Anshuman Suri
Niloofar Mireshghallah
Sewon Min
Weijia Shi
Luke Zettlemoyer
Yulia Tsvetkov
Yejin Choi
David Evans
Hannaneh Hajishirzi


X-LoRA: Mixture of Low-Rank Adapter Experts, a Flexible Framework for Large Language Models with Applications in Protein Mechanics and Molecular Design

Abstract: We report a mixture of expert strategy to create fine-tuned large language models using a deep layer-wise token-level approach based on low-rank adaptation (LoRA). Starting with a set of pre-trained LoRA adapters, our gating strategy uses the hidden states to dynamically mix adapted layers, allowing the resulting X-LoRA model to draw upon different capabilities and create never-before-used deep layer-wise combinations to solve tasks. The design is inspired by the biological principles of universality and diversity, where neural network building blocks are reused in different hierarchical manifestations. Hence, the X-LoRA model can be easily implemented for any existing large language model (LLM) without a need for modifications of the underlying structure. We develop a tailored X-LoRA model that offers scientific capabilities including forward/inverse analysis tasks and enhanced reasoning capability, focused on biomaterial analysis, protein mechanics and design. The impact of this work include access to readily expandable and adaptable models with strong domain knowledge and the capability to integrate across areas of knowledge. Featuring experts in biology, mathematics, reasoning, bio-inspired materials, mechanics and materials, chemistry, protein biophysics, mechanics and quantum-mechanics based molecular properties, we conduct a series of physics-focused case studies. We examine knowledge recall, protein mechanics forward/inverse tasks, protein design, adversarial agentic modeling including ontological knowledge graph construction, as well as molecular design. The model is capable not only of making quantitative predictions of nanomechanical properties of proteins or quantum mechanical molecular properties, but also reasons over the results and correctly predicts likely mechanisms that explain distinct molecular behaviors.


Structure-Informed Protein Language Model

Abstract: Protein language models are a powerful tool for learning protein representations through pre-training on vast protein sequence datasets. However, traditional protein language models lack explicit structural supervision, despite its relevance to protein function. To address this issue, we introduce the integration of remote homology detection to distill structural information into protein language models without requiring explicit protein structures as input. We evaluate the impact of this structure-informed training on downstream protein function prediction tasks. Experimental results reveal consistent improvements in function annotation accuracy for EC number and GO term prediction. Performance on mutant datasets, however, varies based on the relationship between targeted properties and protein structures. This underscores the importance of considering this relationship when applying structure-aware training to protein function prediction tasks. Code and model weights are available at https://github.com/DeepGraphLearning/esm-s.

Zuobai Zhang
Jiarui Lu
Vijil Chenthamarakshan
Aurélie Lozano
Payel Das
Jian Tang


AlphaFold Meets Flow Matching for Generating Protein Ensembles

Abstract: The biological functions of proteins often depend on dynamic structural ensembles. In this work, we develop a flow-based generative modeling approach for learning and sampling the conformational landscapes of proteins. We repurpose highly accurate single-state predictors such as AlphaFold and ESMFold and fine-tune them under a custom flow matching framework to obtain sequence-conditoned generative models of protein structure called AlphaFlow and ESMFlow. When trained and evaluated on the PDB, our method provides a superior combination of precision and diversity compared to AlphaFold with MSA subsampling. When further trained on ensembles from all-atom MD, our method accurately captures conformational flexibility, positional distributions, and higher-order ensemble observables for unseen proteins. Moreover, our method can diversify a static PDB structure with faster wall-clock convergence to certain equilibrium properties than replicate MD trajectories, demonstrating its potential as a proxy for expensive physics-based simulations. Code is available at https://github.com/bjing2016/alphaflow.


Learning immune receptor representations with protein language models

Abstract: Protein language models (PLMs) learn contextual representations from protein sequences and are profoundly impacting various scientific disciplines spanning protein design, drug discovery, and structural predictions. One particular research area where PLMs have gained considerable attention is adaptive immune receptors, whose tremendous sequence diversity dictates the functional recognition of the adaptive immune system. The self-supervised nature underlying the training of PLMs has been recently leveraged to implement a variety of immune receptor-specific PLMs. These models have demonstrated promise in tasks such as predicting antigen-specificity and structure, computationally engineering therapeutic antibodies, and diagnostics. However, challenges including insufficient training data and considerations related to model architecture, training strategies, and data and model availability must be addressed before fully unlocking the potential of PLMs in understanding, translating, and engineering immune receptors.

Andreas Dounas
Tudor-Stefan Cotet
Alexander Yermanos


Detecting Mode Collapse in Language Models via Narration

Abstract: No two authors write alike. Personal flourishes invoked in written narratives, from lexicon to rhetorical devices, imply a particular author--what literary theorists label the implied or virtual author; distinct from the real author or narrator of a text. Early large language models trained on unfiltered training sets drawn from a variety of discordant sources yielded incoherent personalities, problematic for conversational tasks but proving useful for sampling literature from multiple perspectives. Successes in alignment research in recent years have allowed researchers to impose subjectively consistent personae on language models via instruction tuning and reinforcement learning from human feedback (RLHF), but whether aligned models retain the ability to model an arbitrary virtual author has received little scrutiny. By studying 4,374 stories sampled from three OpenAI language models, we show successive versions of GPT-3 suffer from increasing degrees of "mode collapse" whereby overfitting the model during alignment constrains it from generalizing over authorship: models suffering from mode collapse become unable to assume a multiplicity of perspectives. Our method and results are significant for researchers seeking to employ language models in sociological simulations.


idMotif: An Interactive Motif Identification in Protein Sequences

Abstract: This article introduces idMotif, a visual analytics framework designed to aid domain experts in the identification of motifs within protein sequences. Motifs, short sequences of amino acids, are critical for understanding the distinct functions of proteins. Identifying these motifs is pivotal for predicting diseases or infections. idMotif employs a deep learning-based method for the categorization of protein sequences, enabling the discovery of potential motif candidates within protein groups through local explanations of deep learning model decisions. It offers multiple interactive views for the analysis of protein clusters or groups and their sequences. A case study, complemented by expert feedback, illustrates idMotif's utility in facilitating the analysis and identification of protein sequences and motifs.

Ji Hwan Park
Vikash Prasad
Sydney Newsom
Fares Najar
Rakhi Rajan


Enhancing the efficiency of protein language models with minimal wet-lab data through few-shot learning

Abstract: Accurately modeling the protein fitness landscapes holds great importance for protein engineering. Recently, due to their capacity and representation ability, pre-trained protein language models have achieved state-of-the-art performance in predicting protein fitness without experimental data. However, their predictions are limited in accuracy as well as interpretability. Furthermore, such deep learning models require abundant labeled training examples for performance improvements, posing a practical barrier. In this work, we introduce FSFP, a training strategy that can effectively optimize protein language models under extreme data scarcity. By combining the techniques of meta-transfer learning, learning to rank, and parameter-efficient fine-tuning, FSFP can significantly boost the performance of various protein language models using merely tens of labeled single-site mutants from the target protein. The experiments across 87 deep mutational scanning datasets underscore its superiority over both unsupervised and supervised approaches, revealing its potential in facilitating AI-guided protein design.

Ziyi Zhou
Liang Zhang
Yuanxi Yu
Mingchen Li
Liang Hong
Pan Tan


ProtAgents: Protein discovery via large language model multi-agent collaborations combining physics and machine learning

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

Physics
Computer Science
Biology
Medicine


Endowing Protein Language Models with Structural Knowledge

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

Dexiong Chen
Philip Hartout
Paolo Pellizzoni
Carlos Oliver
Karsten Borgwardt


Evolutionary Computation in the Era of Large Language Model: Survey and Roadmap

Abstract: Large language models (LLMs) have not only revolutionized natural language processing but also extended their prowess to various domains, marking a significant stride towards artificial general intelligence. The interplay between LLMs and evolutionary algorithms (EAs), despite differing in objectives and methodologies, share a common pursuit of applicability in complex problems. Meanwhile, EA can provide an optimization framework for LLM's further enhancement under black-box settings, empowering LLM with flexible global search capacities. On the other hand, the abundant domain knowledge inherent in LLMs could enable EA to conduct more intelligent searches. Furthermore, the text processing and generative capabilities of LLMs would aid in deploying EAs across a wide range of tasks. Based on these complementary advantages, this paper provides a thorough review and a forward-looking roadmap, categorizing the reciprocal inspiration into two main avenues: LLM-enhanced EA and EA-enhanced LLM. Some integrated synergy methods are further introduced to exemplify the complementarity between LLMs and EAs in diverse scenarios, including code generation, software engineering, neural architecture search, and various generation tasks. As the first comprehensive review focused on the EA research in the era of LLMs, this paper provides a foundational stepping stone for understanding the collaborative potential of LLMs and EAs. The identified challenges and future directions offer guidance for researchers and practitioners to unlock the full potential of this innovative collaboration in propelling advancements in optimization and artificial intelligence. We have created a GitHub repository to index the relevant papers: https://github.com/wuxingyu-ai/LLM4EC.

Xingyu Wu
Sheng-hao Wu
Jibin Wu
Liang Feng
Kay Chen Tan

IEEE Transactions on Evolutionary Computation


Part-of-Speech Tagger for Bodo Language using Deep Learning approach

Abstract: Language Processing systems such as Part-of-speech tagging, Named entity recognition, Machine translation, Speech recognition, and Language modeling (LM) are well-studied in high-resource languages. Nevertheless, research on these systems for several low-resource languages, including Bodo, Mizo, Nagamese, and others, is either yet to commence or is in its nascent stages. Language model plays a vital role in the downstream tasks of modern NLP. Extensive studies are carried out on LMs for high-resource languages. Nevertheless, languages such as Bodo, Rabha, and Mising continue to lack coverage. In this study, we first present BodoBERT, a language model for the Bodo language. To the best of our knowledge, this work is the first such effort to develop a language model for Bodo. Secondly, we present an ensemble DL-based POS tagging model for Bodo. The POS tagging model is based on combinations of BiLSTM with CRF and stacked embedding of BodoBERT with BytePairEmbeddings. We cover several language models in the experiment to see how well they work in POS tagging tasks. The best-performing model achieves an F1 score of 0.8041. A comparative experiment was also conducted on Assamese POS taggers, considering that the language is spoken in the same region as Bodo.

Dhrubajyoti Pathak
Sanjib Narzary
Sukumar Nandi
Bidisha Som


ACP-ESM: A novel framework for classification of anticancer peptides using protein-oriented transformer approach

Abstract: Anticancer peptides (ACPs) are a class of molecules that have gained significant attention in the field of cancer research and therapy. ACPs are short chains of amino acids, the building blocks of proteins, and they possess the ability to selectively target and kill cancer cells. One of the key advantages of ACPs is their ability to selectively target cancer cells while sparing healthy cells to a greater extent. This selectivity is often attributed to differences in the surface properties of cancer cells compared to normal cells. That is why ACPs are being investigated as potential candidates for cancer therapy. ACPs may be used alone or in combination with other treatment modalities like chemotherapy and radiation therapy. While ACPs hold promise as a novel approach to cancer treatment, there are challenges to overcome, including optimizing their stability, improving selectivity, and enhancing their delivery to cancer cells, continuous increasing in number of peptide sequences, developing a reliable and precise prediction model. In this work, we propose an efficient transformer-based framework to identify anticancer peptides for by performing accurate a reliable and precise prediction model. For this purpose, four different transformer models, namely ESM, ProtBert, BioBERT, and SciBERT are employed to detect anticancer peptides from amino acid sequences. To demonstrate the contribution of the proposed framework, extensive experiments are carried on widely-used datasets in the literature, two versions of AntiCp2, cACP-DeepGram, ACP-740. Experiment results show the usage of proposed model enhances classification accuracy when compared to the state-of-the-art studies. The proposed framework, ESM, exhibits 96.45 of accuracy for AntiCp2 dataset, 97.66 of accuracy for cACP-DeepGram dataset, and 88.51 of accuracy for ACP-740 dataset, thence determining new state-of-the-art.


Identification of Knowledge Neurons in Protein Language Models

Abstract: Neural language models have become powerful tools for learning complex representations of entities in natural language processing tasks. However, their interpretability remains a significant challenge, particularly in domains like computational biology where trust in model predictions is crucial. In this work, we aim to enhance the interpretability of protein language models, specifically the state-of-the-art ESM model, by identifying and characterizing knowledge neurons - components that express understanding of key information. After fine-tuning the ESM model for the task of enzyme sequence classification, we compare two knowledge neuron selection methods that preserve a subset of neurons from the original model. The two methods, activation-based and integrated gradient-based selection, consistently outperform a random baseline. In particular, these methods show that there is a high density of knowledge neurons in the key vector prediction networks of self-attention modules. Given that key vectors specialize in understanding different features of input sequences, these knowledge neurons could capture knowledge of different enzyme sequence motifs. In the future, the types of knowledge captured by each neuron could be characterized.

Divya Nori
Shivali Singireddy
Marina Ten Have


Demystifying Instruction Mixing for Fine-tuning Large Language Models

Abstract: Instruction tuning significantly enhances the performance of large language models (LLMs) across various tasks. However, the procedure to optimizing the mixing of instruction datasets for LLM fine-tuning is still poorly understood. This study categorizes instructions into three primary types: NLP downstream tasks, coding, and general chat. We explore the effects of instruction tuning on different combinations of datasets on LLM performance, and find that certain instruction types are more advantageous for specific applications but can negatively impact other areas. This work provides insights into instruction mixtures, laying the foundations for future research.

Renxi Wang
Haonan Li
Minghao Wu
Yuxia Wang
Xudong Han
Chiyu Zhang
Timothy Baldwin


Beneath the Surface: Unveiling Harmful Memes with Multimodal Reasoning Distilled from Large Language Models

Abstract: The age of social media is rife with memes. Understanding and detecting harmful memes pose a significant challenge due to their implicit meaning that is not explicitly conveyed through the surface text and image. However, existing harmful meme detection approaches only recognize superficial harm-indicative signals in an end-to-end classification manner but ignore in-depth cognition of the meme text and image. In this paper, we attempt to detect harmful memes based on advanced reasoning over the interplay of multimodal information in memes. Inspired by the success of Large Language Models (LLMs) on complex reasoning, we first conduct abductive reasoning with LLMs. Then we propose a novel generative framework to learn reasonable thoughts from LLMs for better multimodal fusion and lightweight fine-tuning, which consists of two training stages: 1) Distill multimodal reasoning knowledge from LLMs; and 2) Fine-tune the generative framework to infer harmfulness. Extensive experiments conducted on three meme datasets demonstrate that our proposed approach achieves superior performance than state-of-the-art methods on the harmful meme detection task.

Hongzhan Lin
Ziyang Luo
Jing Ma
Long Chen


Efficiently Predicting Protein Stability Changes Upon Single-point Mutation with Large Language Models

Abstract: Predicting protein stability changes induced by single-point mutations has been a persistent challenge over the years, attracting immense interest from numerous researchers. The ability to precisely predict protein thermostability is pivotal for various subfields and applications in biochemistry, including drug development, protein evolution analysis, and enzyme synthesis. Despite the proposition of multiple methodologies aimed at addressing this issue, few approaches have successfully achieved optimal performance coupled with high computational efficiency. Two principal hurdles contribute to the existing challenges in this domain. The first is the complexity of extracting and aggregating sufficiently representative features from proteins. The second refers to the limited availability of experimental data for protein mutation analysis, further complicating the comprehensive evaluation of model performance on unseen data samples. With the advent of Large Language Models(LLM), such as the ESM models in protein research, profound interpretation of protein features is now accessibly aided by enormous training data. Therefore, LLMs are indeed to facilitate a wide range of protein research. In our study, we introduce an ESM-assisted efficient approach that integrates protein sequence and structural features to predict the thermostability changes in protein upon single-point mutations. Furthermore, we have curated a dataset meticulously designed to preclude data leakage, corresponding to two extensively employed test datasets, to facilitate a more equitable model comparison.

Yijie Zhang
Zhangyang Gao
Cheng Tan
Stan Z. Li


Using a Large Language Model to generate a Design Structure Matrix

Abstract: The Design Structure Matrix (DSM) is an established method used in dependency modelling, especially in the design of complex engineering systems. The generation of DSM is traditionally carried out through manual means and can involve interviewing experts to elicit critical system elements and the relationships between them. Such manual approaches can be time-consuming and costly. This paper presents a workflow that uses a Large Language Model (LLM) to support the generation of DSM and improve productivity. A prototype of the workflow was developed in this work and applied on a diesel engine DSM published previously. It was found that the prototype could reproduce 357 out of 462 DSM entries published (i.e. 77.3%), suggesting that the work can aid DSM generation. A no-code version of the prototype is made available online to support future research.


Protein Language Model-Powered 3D Ligand Binding Site Prediction from Protein Sequence

Abstract: Prediction of ligand binding sites of proteins is a fundamental and important task for understanding the function of proteins and screening potential drugs. Most existing methods require experimentally determined protein holo-structures as input. However, such structures can be unavailable on novel or less-studied proteins. To tackle this limitation, we propose LaMPSite, which only takes protein sequences and ligand molecular graphs as input for ligand binding site predictions. The protein sequences are used to retrieve residue-level embeddings and contact maps from the pre-trained ESM-2 protein language model. The ligand molecular graphs are fed into a graph neural network to compute atom-level embeddings. Then we compute and update the protein-ligand interaction embedding based on the protein residue-level embeddings and ligand atom-level embeddings, and the geometric constraints in the inferred protein contact map and ligand distance map. A final pooling on protein-ligand interaction embedding would indicate which residues belong to the binding sites. Without any 3D coordinate information of proteins, our proposed model achieves competitive performance compared to baseline methods that require 3D protein structures when predicting binding sites. Given that less than 50% of proteins have reliable structure information in the current stage, LaMPSite will provide new opportunities for drug discovery.


ESM-NBR: fast and accurate nucleic acid-binding residue prediction via protein language model feature representation and multi-task learning

Abstract: Protein-nucleic acid interactions play a very important role in a variety of biological activities. Accurate identification of nucleic acid-binding residues is a critical step in understanding the interaction mechanisms. Although many computationally based methods have been developed to predict nucleic acid-binding residues, challenges remain. In this study, a fast and accurate sequence-based method, called ESM-NBR, is proposed. In ESM-NBR, we first use the large protein language model ESM2 to extract discriminative biological properties feature representation from protein primary sequences; then, a multi-task deep learning model composed of stacked bidirectional long short-term memory (BiLSTM) and multi-layer perceptron (MLP) networks is employed to explore common and private information of DNA- and RNA-binding residues with ESM2 feature as input. Experimental results on benchmark data sets demonstrate that the prediction performance of ESM2 feature representation comprehensively outperforms evolutionary information-based hidden Markov model (HMM) features. Meanwhile, the ESM-NBR obtains the MCC values for DNA-binding residues prediction of 0.427 and 0.391 on two independent test sets, which are 18.61 and 10.45% higher than those of the second-best methods, respectively. Moreover, by completely discarding the time-cost multiple sequence alignment process, the prediction speed of ESM-NBR far exceeds that of existing methods (5.52s for a protein sequence of length 500, which is about 16 times faster than the second-fastest method). A user-friendly standalone package and the data of ESM-NBR are freely available for academic use at: https://github.com/wwzll123/ESM-NBR.

Wenwu Zeng
Dafeng Lv
Wenjuan Liu
Shaoliang Peng

IEEE International Conference on Bioinformatics and Biomedicine


A perspective on protein structure prediction using quantum computers

Abstract: Despite the recent advancements by deep learning methods such as AlphaFold2, \textit{in silico} protein structure prediction remains a challenging problem in biomedical research. With the rapid evolution of quantum computing, it is natural to ask whether quantum computers can offer some meaningful benefits for approaching this problem. Yet, identifying specific problem instances amenable to quantum advantage, and estimating quantum resources required are equally challenging tasks. Here, we share our perspective on how to create a framework for systematically selecting protein structure prediction problems that are amenable for quantum advantage, and estimate quantum resources for such problems on a utility-scale quantum computer. As a proof-of-concept, we validate our problem selection framework by accurately predicting the structure of a catalytic loop of the Zika Virus NS3 Helicase, on quantum hardware.

Hakan Doga
Bryan Raubenolt
Fabio Cumbo
Jayadev Joshi
Frank P. DiFilippo
Jun Qin
Daniel Blankenberg
Omar Shehab

Journal of Chemical Theory and Computation


Acoustic Prompt Tuning: Empowering Large Language Models with Audition Capabilities

Abstract: The auditory system plays a substantial role in shaping the overall human perceptual experience. While prevailing large language models (LLMs) and visual language models (VLMs) have shown their promise in solving a wide variety of language and vision understanding tasks, only a few of them can be generalised to the audio domain without compromising their domain-specific capability. In this work, we introduce Acoustic Prompt Tuning (APT), a new adapter extending LLMs and VLMs to the audio domain by injecting audio embeddings to the input of LLMs, namely soft prompting. Specifically, APT applies an instruction-aware audio aligner to generate soft prompts, conditioned on both input text and sounds, as the inputs to the language model. To mitigate data scarcity in the audio domain, a curriculum learning strategy is proposed by formulating diverse audio tasks in a sequential manner. Moreover, we improve the audio language model by using interleaved audio-text embeddings as the input sequence. In this improved model, zero constraints are imposed on the input format, thus it is capable of tackling diverse modelling tasks, such as few-shot audio classification and audio comparison. To further evaluate the advanced ability of the audio networks, we introduce natural language audio reasoning (NLAR), a new task that analyses two audio clips by comparison and summarisation. Experiments show that APT-enhanced LLMs (namely APT-LLMs) achieve competitive results compared to the expert models (i.e., the networks trained on the target datasets) across various tasks. We finally demonstrate APT's ability in extending frozen VLMs to the audio domain without fine-tuning, achieving promising results in audio-visual question and answering. Our code and model weights will be released at https://github.com/JinhuaLiang/APT

Jinhua Liang
Xubo Liu
Wenwu Wang
Mark D. Plumbley
Huy Phan
Emmanouil Benetos

IEEE Transactions on Audio, Speech, and Language Processing


When a Language Question Is at Stake. A Revisited Approach to Label Sensitive Content

Abstract: Many under-resourced languages require high-quality datasets for specific tasks such as offensive language detection, disinformation, or misinformation identification. However, the intricacies of the content may have a detrimental effect on the annotators. The article aims to revisit an approach of pseudo-labeling sensitive data on the example of Ukrainian tweets covering the Russian-Ukrainian war. Nowadays, this acute topic is in the spotlight of various language manipulations that cause numerous disinformation and profanity on social media platforms. The conducted experiment highlights three main stages of data annotation and underlines the main obstacles during machine annotation. Ultimately, we provide a fundamental statistical analysis of the obtained data, evaluation of models used for pseudo-labelling, and set further guidelines on how the scientists can leverage the corpus to execute more advanced research and extend the existing data samples without annotators' engagement.


Efficiently Adapting Pretrained Language Models To New Languages

Abstract: Recent large language models (LLM) exhibit sub-optimal performance on low-resource languages, as the training data of these models is usually dominated by English and other high-resource languages. Furthermore, it is challenging to train models for low-resource languages, especially from scratch, due to a lack of high quality training data. Adapting pretrained LLMs reduces the need for data in the new language while also providing cross lingual transfer capabilities. However, naively adapting to new languages leads to catastrophic forgetting and poor tokenizer efficiency. In this work, we study how to efficiently adapt any existing pretrained LLM to a new language without running into these issues. In particular, we improve the encoding efficiency of the tokenizer by adding new tokens from the target language and study the data mixing recipe to mitigate forgetting. Our experiments on adapting an English LLM to Hungarian and Thai show that our recipe can reach better performance than open source models on the target language, with minimal regressions on English.

Zoltan Csaki
Pian Pawakapan
Urmish Thakker
Qiantong Xu


Impact of the Ce $4f$ states in the electronic structure of the intermediate-valence superconductor CeIr$_3$

Abstract: The electronic structure of the $f$-based superconductor $\mathrm{CeIr_3}$ was studied by photoelectron spectroscopy. The energy distribution of the $\mathrm{Ce}~4f$ states were revealed by the $\mathrm{Ce}~3d-4f$ resonant photoelectron spectroscopy. The $\mathrm{Ce}~4f$ states were mostly distributed in the vicinity of the Fermi energy, suggesting the itinerant character of the $\mathrm{Ce}~4f$ states. The contribution of the $\mathrm{Ce}~4f$ states to the density of states (DOS) at the Fermi energy was estimated to be nearly half of that of the $\mathrm{Ir}~5d$ states, implying that the $\mathrm{Ce}~4f$ states have a considerable contribution to the DOS at the Fermi energy. The $\mathrm{Ce}~3d$ core-level and $\mathrm{Ce}~3d$ X-ray absorption spectra were analyzed based on a single-impurity Anderson model. The number of the $\mathrm{Ce}~4f$ states in the ground state was estimated to be $0.8-0.9$, which is much larger than the values obtained in the previous studies (i.e., $0-0.4$).

Shin-ichi Fujimori
Ikuto Kawasaki
Yukiharu Takeda
Hiroshi Yamagami
Norimasa Sasabe
Yoshiki J. Sato
Ai Nakamura
Yusei Shimizu
Arvind Maurya
Yoshiya Homma
Dexin Li
Fuminori Honda
Dai Aoki


Can Language Models Be Tricked by Language Illusions? Easier with Syntax, Harder with Semantics

Abstract: Language models (LMs) have been argued to overlap substantially with human beings in grammaticality judgment tasks. But when humans systematically make errors in language processing, should we expect LMs to behave like cognitive models of language and mimic human behavior? We answer this question by investigating LMs' more subtle judgments associated with "language illusions" -- sentences that are vague in meaning, implausible, or ungrammatical but receive unexpectedly high acceptability judgments by humans. We looked at three illusions: the comparative illusion (e.g. "More people have been to Russia than I have"), the depth-charge illusion (e.g. "No head injury is too trivial to be ignored"), and the negative polarity item (NPI) illusion (e.g. "The hunter who no villager believed to be trustworthy will ever shoot a bear"). We found that probabilities represented by LMs were more likely to align with human judgments of being "tricked" by the NPI illusion which examines a structural dependency, compared to the comparative and the depth-charge illusions which require sophisticated semantic understanding. No single LM or metric yielded results that are entirely consistent with human behavior. Ultimately, we show that LMs are limited both in their construal as cognitive models of human language processing and in their capacity to recognize nuanced but critical information in complicated language materials.


Exploring Post-Training Quantization of Protein Language Models

Abstract: Recent advancements in unsupervised protein language models (ProteinLMs), like ESM-1b and ESM-2, have shown promise in different protein prediction tasks. However, these models face challenges due to their high computational demands, significant memory needs, and latency, restricting their usage on devices with limited resources. To tackle this, we explore post-training quantization (PTQ) for ProteinLMs, focusing on ESMFold, a simplified version of AlphaFold based on ESM-2 ProteinLM. Our study is the first attempt to quantize all weights and activations of ProteinLMs. We observed that the typical uniform quantization method performs poorly on ESMFold, causing a significant drop in TM-Score when using 8-bit quantization. We conducted extensive quantization experiments, uncovering unique challenges associated with ESMFold, particularly highly asymmetric activation ranges before Layer Normalization, making representation difficult using low-bit fixed-point formats. To address these challenges, we propose a new PTQ method for ProteinLMs, utilizing piecewise linear quantization for asymmetric activation values to ensure accurate approximation. We demonstrated the effectiveness of our method in protein structure prediction tasks, demonstrating that ESMFold can be accurately quantized to low-bit widths without compromising accuracy. Additionally, we applied our method to the contact prediction task, showcasing its versatility. In summary, our study introduces an innovative PTQ method for ProteinLMs, addressing specific quantization challenges and potentially leading to the development of more efficient ProteinLMs with significant implications for various protein-related applications.

Shuang Peng
Fei Yang
Ning Sun
Sheng Chen
Yanfeng Jiang
Aimin Pan


GPCR-BERT: Interpreting Sequential Design of G Protein Coupled Receptors Using Protein Language Models

Abstract: With the rise of Transformers and Large Language Models (LLMs) in Chemistry and Biology, new avenues for the design and understanding of therapeutics have opened up to the scientific community. Protein sequences can be modeled as language and can take advantage of recent advances in LLMs, specifically with the abundance of our access to the protein sequence datasets. In this paper, we developed the GPCR-BERT model for understanding the sequential design of G Protein-Coupled Receptors (GPCRs). GPCRs are the target of over one-third of FDA-approved pharmaceuticals. However, there is a lack of comprehensive understanding regarding the relationship between amino acid sequence, ligand selectivity, and conformational motifs (such as NPxxY, CWxP, E/DRY). By utilizing the pre-trained protein model (Prot-Bert) and fine-tuning with prediction tasks of variations in the motifs, we were able to shed light on several relationships between residues in the binding pocket and some of the conserved motifs. To achieve this, we took advantage of attention weights, and hidden states of the model that are interpreted to extract the extent of contributions of amino acids in dictating the type of masked ones. The fine-tuned models demonstrated high accuracy in predicting hidden residues within the motifs. In addition, the analysis of embedding was performed over 3D structures to elucidate the higher-order interactions within the conformations of the receptors.

Seongwon Kim
Parisa Mollaei
Akshay Antony
Rishikesh Magar
Amir Barati Farimani


Large Language Models and Multimodal Retrieval for Visual Word Sense Disambiguation

Abstract: Visual Word Sense Disambiguation (VWSD) is a novel challenging task with the goal of retrieving an image among a set of candidates, which better represents the meaning of an ambiguous word within a given context. In this paper, we make a substantial step towards unveiling this interesting task by applying a varying set of approaches. Since VWSD is primarily a text-image retrieval task, we explore the latest transformer-based methods for multimodal retrieval. Additionally, we utilize Large Language Models (LLMs) as knowledge bases to enhance the given phrases and resolve ambiguity related to the target word. We also study VWSD as a unimodal problem by converting to text-to-text and image-to-image retrieval, as well as question-answering (QA), to fully explore the capabilities of relevant models. To tap into the implicit knowledge of LLMs, we experiment with Chain-of-Thought (CoT) prompting to guide explainable answer generation. On top of all, we train a learn to rank (LTR) model in order to combine our different modules, achieving competitive ranking results. Extensive experiments on VWSD demonstrate valuable insights to effectively drive future directions.

Anastasia Kritharoula
Maria Lymperaiou
Giorgos Stamou


ForceGen: End-to-end de novo protein generation based on nonlinear mechanical unfolding responses using a protein language diffusion model

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

Computer Science
Physics
Biology
Medicine


Joint Music and Language Attention Models for Zero-shot Music Tagging

Abstract: Music tagging is a task to predict the tags of music recordings. However, previous music tagging research primarily focuses on close-set music tagging tasks which can not be generalized to new tags. In this work, we propose a zero-shot music tagging system modeled by a joint music and language attention (JMLA) model to address the open-set music tagging problem. The JMLA model consists of an audio encoder modeled by a pretrained masked autoencoder and a decoder modeled by a Falcon7B. We introduce preceiver resampler to convert arbitrary length audio into fixed length embeddings. We introduce dense attention connections between encoder and decoder layers to improve the information flow between the encoder and decoder layers. We collect a large-scale music and description dataset from the internet. We propose to use ChatGPT to convert the raw descriptions into formalized and diverse descriptions to train the JMLA models. Our proposed JMLA system achieves a zero-shot audio tagging accuracy of $ 64.82\% $ on the GTZAN dataset, outperforming previous zero-shot systems and achieves comparable results to previous systems on the FMA and the MagnaTagATune datasets.

Xingjian Du
Zhesong Yu
Jiaju Lin
Bilei Zhu
Qiuqiang Kong

IEEE International Conference on Acoustics, Speech, and Signal Processing


Protein 3D Graph Structure Learning for Robust Structure-based Protein Property Prediction

Abstract: Protein structure-based property prediction has emerged as a promising approach for various biological tasks, such as protein function prediction and sub-cellular location estimation. The existing methods highly rely on experimental protein structure data and fail in scenarios where these data are unavailable. Predicted protein structures from AI tools (e.g., AlphaFold2) were utilized as alternatives. However, we observed that current practices, which simply employ accurately predicted structures during inference, suffer from notable degradation in prediction accuracy. While similar phenomena have been extensively studied in general fields (e.g., Computer Vision) as model robustness, their impact on protein property prediction remains unexplored. In this paper, we first investigate the reason behind the performance decrease when utilizing predicted structures, attributing it to the structure embedding bias from the perspective of structure representation learning. To study this problem, we identify a Protein 3D Graph Structure Learning Problem for Robust Protein Property Prediction (PGSL-RP3), collect benchmark datasets, and present a protein Structure embedding Alignment Optimization framework (SAO) to mitigate the problem of structure embedding bias between the predicted and experimental protein structures. Extensive experiments have shown that our framework is model-agnostic and effective in improving the property prediction of both predicted structures and experimental structures. The benchmark datasets and codes will be released to benefit the community.

Yufei Huang
Siyuan Li
Jin Su
Lirong Wu
Odin Zhang
Haitao Lin
Jingqi Qi
Zihan Liu
Zhangyang Gao
Yuyang Liu
Jiangbin Zheng
Stan. ZQ. Li