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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

We propose an energy-based model (EBM) of protein conformations that operates at atomic scale. The model is trained solely on crystallized protein data. By contrast, existing approaches for scoring conformations use energy functions that…

Machine Learning · Computer Science 2020-04-29 Yilun Du , Joshua Meier , Jerry Ma , Rob Fergus , Alexander Rives

Proteins are dynamic, adopting ensembles of conformations. The nature of this conformational heterogenity is imprinted in the raw electron density measurements obtained from X-ray crystallography experiments. Fitting an ensemble of protein…

Quantitative Methods · Quantitative Biology 2024-12-19 Sai Advaith Maddipatla , Nadav Bojan Sellam , Sanketh Vedula , Ailie Marx , Alex Bronstein

Accurate exploration of protein conformational ensembles is essential for uncovering function but remains hard because molecular-dynamics (MD) simulations suffer from high computational costs and energy-barrier trapping. This paper presents…

Machine Learning · Computer Science 2025-11-14 Yuancheng Sun , Yuxuan Ren , Zhaoming Chen , Xu Han , Kang Liu , Qiwei Ye

Searching through chemical space is an exceptionally challenging problem because the number of possible molecules grows combinatorially with the number of atoms. Large, autoregressive models trained on databases of chemical compounds have…

Machine Learning · Computer Science 2025-10-24 Shriram Chennakesavalu , Frank Hu , Sebastian Ibarraran , Grant M. Rotskoff

The Electron Microscopy Data Bank (EMDB) is a rapidly growing repository for the dissemination of structural data from single-particle reconstructions of supramolecular protein assemblies including motors, chaperones, cytoskeletal…

Biomolecules · Quantitative Biology 2010-01-06 Do-Nyun Kim , Cong-Tri Nguyen , Mark Bathe

Current state-of-the-art generative models map noise to data distributions by matching flows or scores. A key limitation of these models is their inability to readily integrate available partial observations and additional priors. In…

Accurate protein structure prediction from amino-acid sequences is critical to better understanding the protein function. Recent advances in this area largely benefit from more precise inter-residue distance and orientation predictions,…

Machine Learning · Computer Science 2021-06-01 Jiaxiang Wu , Shitong Luo , Tao Shen , Haidong Lan , Sheng Wang , Junzhou Huang

Proteins exist as a dynamic ensemble of multiple conformations, and these motions are often crucial for their functions. However, current structure prediction methods predominantly yield a single conformation, overlooking the conformational…

Biomolecules · Quantitative Biology 2025-06-18 Advaith Maddipatla , Nadav Bojan Sellam , Meital Bojan , Sanketh Vedula , Paul Schanda , Ailie Marx , Alex M. Bronstein

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

Understanding the dynamic behavior of proteins is critical to elucidating their functional mechanisms, yet generating realistic, temporally coherent trajectories of protein ensembles remains a significant challenge. In this work, we…

Biomolecules · Quantitative Biology 2025-11-11 Yaoyao Xu , Di Wang , Zihan Zhou , Tianshu Yu , Mingchen Chen

Protein dynamics underlie many biological functions, yet remain difficult to characterize due to the high computational cost of molecular dynamics simulations and the scarcity of dynamic structural data. This survey reviews recent advances…

Biomolecules · Quantitative Biology 2026-04-29 Haocheng Tang , Liang Shi , Ya-Shi Zhang , Xixian Liu , Jian Tang , Jiarui Lu

Excitement at the prospect of using data-driven generative models to sample configurational ensembles of biomolecular systems stems from the extraordinary success of these models on a diverse set of high-dimensional sampling tasks. Unlike…

Statistical Mechanics · Physics 2024-02-06 Shriram Chennakesavalu , Grant M. Rotskoff

The rapid evolution of molecular dynamics (MD) methods, including machine-learned dynamics, has outpaced the development of standardized tools for method validation. Objective comparison between simulation approaches is often hindered by…

The protein dynamics are common and important for their biological functions and properties, the study of which usually involves time-consuming molecular dynamics (MD) simulations in silico. Recently, generative models has been leveraged as…

Biomolecules · Quantitative Biology 2024-03-13 Jiarui Lu , Zuobai Zhang , Bozitao Zhong , Chence Shi , Jian Tang

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

Energy-based models (EBMs) are generative models inspired by statistical physics with a wide range of applications in unsupervised learning. Their performance is best measured by the cross-entropy (CE) of the model distribution relative to…

Machine Learning · Computer Science 2023-12-14 Davide Carbone , Mengjian Hua , Simon Coste , Eric Vanden-Eijnden

Predicting changes in binding free energy ($\Delta\Delta G$) is a vital task in protein engineering and protein-protein interaction (PPI) engineering for drug discovery. Previous works have observed a high correlation between $\Delta\Delta…

Machine Learning · Computer Science 2025-08-15 Patrick Soga , Zhenyu Lei , Yinhan He , Camille Bilodeau , Jundong Li

Advances in deep learning have opened an era of abundant and accurate predicted protein structures; however, similar progress in protein ensembles has remained elusive. This review highlights several recent research directions towards…

Biomolecules · Quantitative Biology 2025-09-23 Bowen Jing , Bonnie Berger , Tommi Jaakkola

Energy-based models (EBMs) provide a powerful and flexible way of learning a joint probability distribution over data by constructing an energy surface. This energy surface enables insight extraction and conditional sampling. We apply EBMs…

Plasma Physics · Physics 2026-05-12 Phil Travis , Troy Carter
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