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Protein language models often take into consideration the alignment between a protein sequence and its textual description. However, they do not take structural information into consideration. Traditional methods treat sequence and…

Machine Learning · Computer Science 2026-03-10 Aditya Ranganath , Hasin Us Sami , Kowshik Thopalli , Bhavya Kailkhura , Wesam Sakla

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…

Biomolecules · Quantitative Biology 2024-09-04 Bowen Jing , Bonnie Berger , Tommi Jaakkola

While protein language models (PLMs) are one of the most promising avenues of research for future de novo protein design, the way in which they transform sequences to hidden representations, as well as the information encoded in such…

Machine Learning · Computer Science 2026-05-29 Kosio Beshkov , Anders Malthe-Sørenssen

Proteins move and deform to ensure their biological functions. Despite significant progress in protein structure prediction, approximating conformational ensembles at physiological conditions remains a fundamental open problem. This paper…

Biomolecules · Quantitative Biology 2025-04-07 Valentin Lombard , Sergei Grudinin , Elodie Laine

Generative modeling has become a central paradigm in protein research, extending machine learning beyond structure prediction toward sequence design, backbone generation, inverse folding, and biomolecular interaction modeling. However, the…

Machine Learning · Computer Science 2026-03-30 Senura Hansaja Wanasekara , Minh-Duong Nguyen , Xiaochen Liu , Nguyen H. Tran , Ken-Tye Yong

We introduce RosettaSearch, an inference-time multi-objective optimization approach for backbone conditioned protein sequence design. We use large language models (LLMs) as a generative optimizer within a search algorithm capable of…

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

Multimodal protein language models (PLMs) integrate sequence and token-based structural information, serving as a powerful foundation for protein modeling, generation, and design. However, the reliance on tokenizing 3D structures into…

Machine Learning · Computer Science 2025-06-13 Cheng-Yen Hsieh , Xinyou Wang , Daiheng Zhang , Dongyu Xue , Fei Ye , Shujian Huang , Zaixiang Zheng , Quanquan Gu

Protein language models learn powerful representations directly from sequences of amino acids. However, they are constrained to generate proteins with only the set of amino acids represented in their vocabulary. In contrast, chemical…

Biomolecules · Quantitative Biology 2023-08-21 Daniel Flam-Shepherd , Kevin Zhu , Alán Aspuru-Guzik

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein function or structure. Existing approaches usually pretrain protein language models on a large number of unlabeled amino acid…

Machine Learning · Computer Science 2023-01-31 Zuobai Zhang , Minghao Xu , Arian Jamasb , Vijil Chenthamarakshan , Aurelie Lozano , Payel Das , Jian Tang

Machine learning (ML)-guided directed evolution is a new paradigm for biological design that enables optimization of complex functions. ML methods use data to predict how sequence maps to function without requiring a detailed model of the…

Biomolecules · Quantitative Biology 2019-04-23 Kevin K. Yang , Zachary Wu , Frances H. Arnold

The conditional generation of proteins with desired functions is a key goal for generative models. Existing methods based on prompting of protein language models (PLMs) can generate proteins conditioned on a target functionality, such as a…

Biomolecules · Quantitative Biology 2025-06-13 Jason Yang , Aadyot Bhatnagar , Jeffrey A. Ruffolo , Ali Madani

Protein design has become a critical method in advancing significant potential for various applications such as drug development and enzyme engineering. However, protein design methods utilizing large language models with solely pretraining…

Artificial Intelligence · Computer Science 2024-12-06 Xiao-Yu Guo , Yi-Fan Li , Yuan Liu , Xiaoyong Pan , Hong-Bin Shen

Biological processes, functions, and properties are intricately linked to the ensemble of protein conformations, rather than being solely determined by a single stable conformation. In this study, we have developed P2DFlow, a generative…

Biological Physics · Physics 2025-03-05 Yaowei Jin , Qi Huang , Ziyang Song , Mingyue Zheng , Dan Teng , Qian Shi

We explore optimally training protein language models, an area of significant interest in biological research where guidance on best practices is limited. Most models are trained with extensive compute resources until performance gains…

Machine Learning · Computer Science 2024-11-05 Xingyi Cheng , Bo Chen , Pan Li , Jing Gong , Jie Tang , Le Song

This work introduces the generative fractional diffusion model for protein generation (ProT-GFDM), a novel generative framework that employs fractional stochastic dynamics for protein backbone structure modeling. This approach builds on the…

Quantitative Methods · Quantitative Biology 2025-05-01 Xiao Liang , Wentao Ma , Eric Paquet , Herna Lydia Viktor , Wojtek Michalowski

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in…

Genomics · Quantitative Biology 2025-02-19 Wang Liang

Statistical analysis of evolutionary-related protein sequences provides insights about their structure, function, and history. We show that Restricted Boltzmann Machines (RBM), designed to learn complex high-dimensional data and their…

Quantitative Methods · Quantitative Biology 2019-02-28 Jérôme Tubiana , Simona Cocco , Rémi Monasson

The advancement of the Natural Language Processing field has enabled the development of language models with a great capacity for generating text. In recent years, Neuroscience has been using these models to better understand cognitive…

Neurons and Cognition · Quantitative Biology 2024-10-01 Bruno Bianchi , Alfredo Umfurer , Juan Esteban Kamienkowski

Post-translational modifications (PTMs) form a combinatorial "code" that regulates protein function, yet deciphering this code - linking modified sites to their catalytic enzymes - remains a central unsolved problem in understanding…

Computational Engineering, Finance, and Science · Computer Science 2025-10-28 Jingjie Zhang , Hanqun Cao , Zijun Gao , Yu Wang , Shaoning Li , Jun Xu , Cheng Tan , Jun Zhu , Chang-Yu Hsieh , Chunbin Gu , Pheng Ann Heng