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Protein Language Models (PLMs), pre-trained on extensive evolutionary data from natural proteins, have emerged as indispensable tools for protein design. While powerful, PLMs often struggle to produce proteins with precisely specified…

Biomolecules · Quantitative Biology 2025-09-15 Long-Kai Huang , Rongyi Zhu , Bing He , Jianhua Yao

The design of protein sequences with desired functionalities is a fundamental task in protein engineering. Deep generative methods, such as autoregressive models and diffusion models, have greatly accelerated the discovery of novel protein…

Machine Learning · Computer Science 2025-04-16 Zitai Kong , Yiheng Zhu , Yinlong Xu , Hanjing Zhou , Mingzhe Yin , Jialu Wu , Hongxia Xu , Chang-Yu Hsieh , Tingjun Hou , Jian Wu

Single-cell foundation models (scFMs) have demonstrated state-of-the-art performance on various tasks, such as cell-type annotation and perturbation response prediction, by learning gene regulatory networks from large-scale transcriptome…

Machine Learning · Computer Science 2025-09-19 Sosuke Hosokawa , Toshiharu Kawakami , Satoshi Kodera , Masamichi Ito , Norihiko Takeda

Computational biology and bioinformatics provide vast data gold-mines from protein sequences, ideal for Language Models taken from NLP. These LMs reach for new prediction frontiers at low inference costs. Here, we trained two…

Protein language models (pLMs) pre-trained on vast protein sequence databases excel at various downstream tasks but often lack the structural knowledge essential for some biological applications. To address this, we introduce a method to…

Protein homology search underlies function annotation, structure prediction, and evolutionary analysis, but remains challenging in the "twilight zone," where global sequence similarity is weak and classical alignment methods lose…

Machine Learning · Computer Science 2026-05-29 Gabrielle Cohn , Rohan Gumaste , Minh Hoang , Vihan Lakshman

Studying protein mutations within amino acid sequences holds tremendous significance in life sciences. Protein language models (PLMs) have demonstrated strong capabilities in broad biological applications. However, due to architectural…

Machine Learning · Computer Science 2024-10-31 Yizhen Luo , Zikun Nie , Massimo Hong , Suyuan Zhao , Hao Zhou , Zaiqing Nie

Predicting the structure of interacting chains is crucial for understanding biological systems and developing new drugs. Large-scale pre-trained Protein Language Models (PLMs), such as ESM2, have shown impressive abilities in extracting…

Biomolecules · Quantitative Biology 2023-12-05 Shuxian Zou , Hui Li , Shentong Mo , Xingyi Cheng , Eric Xing , Le Song

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates…

Machine Learning · Computer Science 2024-10-18 Xinyou Wang , Zaixiang Zheng , Fei Ye , Dongyu Xue , Shujian Huang , Quanquan Gu

Many features in pretrained Transformers span multiple layers: they emerge through stages of inference, persist in the residual stream, or are built jointly by parallel MLPs. Crosscoders (namely, sparse dictionaries trained jointly across…

Machine Learning · Computer Science 2026-05-12 Andreas D. Demou , Panagiotis Koromilas , James Oldfield , Yannis Panagakis , Mihalis A. Nicolaou

Protein language models (PLMs) encode rich biological information, yet their internal neuron representations are poorly understood. We introduce the first automated framework for labeling every neuron in a PLM with biologically grounded…

Machine Learning · Computer Science 2025-07-10 Arjun Banerjee , David Martinez , Camille Dang , Ethan Tam

Existing Protein Language Models (PLMs) often suffer from limited adaptability to multiple tasks and exhibit poor generalization across diverse biological contexts. In contrast, general-purpose Large Language Models (LLMs) lack the…

Machine Learning · Computer Science 2026-02-23 Yujia Wang , Jihong Guan , Wengen Li , Shuigeng Zhou , Xuhong Wang

Understanding biological processes, drug development, and biotechnological advancements requires a detailed analysis of protein structures and functions, a task that is inherently complex and time-consuming in traditional protein research.…

Artificial Intelligence · Computer Science 2025-04-21 Yijia Xiao , Edward Sun , Yiqiao Jin , Qifan Wang , Wei Wang

The parallels between protein sequences and natural language in their sequential structures have inspired the application of large language models (LLMs) to protein understanding. Despite the success of LLMs in NLP, their effectiveness in…

Quantitative Methods · Quantitative Biology 2024-07-09 Yiqing Shen , Zan Chen , Michail Mamalakis , Luhan He , Haiyang Xia , Tianbin Li , Yanzhou Su , Junjun He , Yu Guang Wang

Current protein language models (PLMs) learn protein representations mainly based on their sequences, thereby well capturing co-evolutionary information, but they are unable to explicitly acquire protein functions, which is the end goal of…

Biomolecules · Quantitative Biology 2023-07-06 Minghao Xu , Xinyu Yuan , Santiago Miret , Jian Tang

Deciphering the function of unseen protein sequences is a fundamental challenge with broad scientific impact, yet most existing methods depend on task-specific adapters or large-scale supervised fine-tuning. We introduce the…

Machine Learning · Computer Science 2025-10-14 Xinhui Chen , Zuchao Li , Mengqi Gao , Yufeng Zhang , Chak Tou Leong , Haoyang Li , Jiaqi Chen

Protein representation learning (PRL) is crucial for understanding structure-function relationships, yet current sequence- and graph-based methods fail to capture the hierarchical organization inherent in protein structures. We introduce…

Machine Learning · Computer Science 2025-09-05 Zhiyu Wang , Arian Jamasb , Mustafa Hajij , Alex Morehead , Luke Braithwaite , Pietro Liò

Proteins are fundamental to biology, executing diverse functions through complex physicochemical interactions, and they hold transformative potential across medicine, materials science, and environmental applications. Protein Language…

Biomolecules · Quantitative Biology 2025-06-11 Logan Hallee , Nikolaos Rafailidis , David B. Bichara , Jason P. Gleghorn

Masked language modelling (MLM) as a pretraining objective has been widely adopted in genomic sequence modelling. While pretrained models can successfully serve as encoders for various downstream tasks, the distribution shift between…

Machine Learning · Computer Science 2025-02-26 Monireh Safari , Pablo Millan Arias , Scott C. Lowe , Lila Kari , Angel X. Chang , Graham W. Taylor

Considering the significance of proteins, computational protein science has always been a critical scientific field, dedicated to revealing knowledge and developing applications within the protein sequence-structure-function paradigm. In…

Computational Engineering, Finance, and Science · Computer Science 2025-01-28 Wenqi Fan , Yi Zhou , Shijie Wang , Yuyao Yan , Hui Liu , Qian Zhao , Le Song , Qing Li