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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 present FrameFlow, a method for fast protein backbone generation using SE(3) flow matching. Specifically, we adapt FrameDiff, a state-of-the-art diffusion model, to the flow-matching generative modeling paradigm. We show how flow…

The computational design of novel protein structures has the potential to impact numerous scientific disciplines greatly. Toward this goal, we introduce FoldFlow, a series of novel generative models of increasing modeling power based on the…

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

Protein design often begins with the knowledge of a desired function from a motif which motif-scaffolding aims to construct a functional protein around. Recently, generative models have achieved breakthrough success in designing scaffolds…

Recent advances in geometric deep learning and generative modeling have enabled the design of novel proteins with a wide range of desired properties. However, current state-of-the-art approaches are typically restricted to generating…

Biomolecules · Quantitative Biology 2025-08-26 Vsevolod Viliuga , Leif Seute , Nicolas Wolf , Simon Wagner , Arne Elofsson , Jan Stühmer , Frauke Gräter

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

Molecular structure generation is a fundamental problem that involves determining the 3D positions of molecules' constituents. It has crucial biological applications, such as molecular docking, protein folding, and molecular design. Recent…

Machine Learning · Computer Science 2025-08-27 Wenyin Zhou , Christopher Iliffe Sprague , Vsevolod Viliuga , Matteo Tadiello , Arne Elofsson , Hossein Azizpour

Generative modeling techniques such as Diffusion and Flow Matching have achieved significant successes in generating designable and diverse protein backbones. However, many current models are computationally expensive, requiring hundreds or…

Biomolecules · Quantitative Biology 2025-10-30 Junhua Chen , Simon Mathis , Charles Harris , Kieran Didi , Pietro Lio

We propose Pullback Flow Matching (PFM), a novel framework for generative modeling on data manifolds. Unlike existing methods that assume or learn restrictive closed-form manifold mappings for training Riemannian Flow Matching (RFM) models,…

Machine Learning · Computer Science 2025-07-10 Friso de Kruiff , Erik Bekkers , Ozan Öktem , Carola-Bibiane Schönlieb , Willem Diepeveen

We introduce a generative model for protein backbone design utilizing geometric products and higher order message passing. In particular, we propose Clifford Frame Attention (CFA), an extension of the invariant point attention (IPA)…

Machine Learning · Computer Science 2024-11-11 Simon Wagner , Leif Seute , Vsevolod Viliuga , Nicolas Wolf , Frauke Gräter , Jan Stühmer

Protein backbone generation plays a central role in de novo protein design and is significant for many biological and medical applications. Although diffusion and flow-based generative models provide potential solutions to this challenging…

Machine Learning · Computer Science 2025-05-29 Angxiao Yue , Zichong Wang , Hongteng Xu

Proteins are essential for almost all biological processes and derive their diverse functions from complex 3D structures, which are in turn determined by their amino acid sequences. In this paper, we exploit the rich biological inductive…

Protein sequence generation for engineering requires samples that are biophysically plausible and, when targeting a family/domain, remain recognizable members while exploring within-family diversity. Current discrete generative models…

Computational Engineering, Finance, and Science · Computer Science 2026-05-25 Langzhang Liang , Ming Yang , Yi Feng , Junfan Li , Shirui Pan , Yinghui Xu , Tianlei Ying , Yizhen Zheng , Zenglin Xu

Protein family design emerges as a promising alternative by combining the advantages of de novo protein design and mutation-based directed evolution.In this paper, we propose ProfileBFN, the Profile Bayesian Flow Networks, for specifically…

Biomolecules · Quantitative Biology 2025-02-25 Jingjing Gong , Yu Pei , Siyu Long , Yuxuan Song , Zhe Zhang , Wenhao Huang , Ziyao Cao , Shuyi Zhang , Hao Zhou , Wei-Ying Ma

Designing novel proteins that bind to small molecules is a long-standing challenge in computational biology, with applications in developing catalysts, biosensors, and more. Current computational methods rely on the assumption that the…

Biomolecules · Quantitative Biology 2024-09-19 Junqi Liu , Shaoning Li , Chence Shi , Zhi Yang , Jian Tang

Estimating three-dimensional conformations of a molecular graph allows insight into the molecule's biological and chemical functions. Fast generation of valid conformations is thus central to molecular modeling. Recent advances in…

Machine Learning · Computer Science 2025-02-18 Sohil Atul Shah , Vladlen Koltun

Diffusion and flow models have become the dominant paradigm for generative modeling on Riemannian manifolds, with successful applications in protein backbone generation and DNA sequence design. However, these methods require tens to…

Machine Learning · Computer Science 2026-05-04 Dongyeop Woo , Marta Skreta , Seonghyun Park , Kirill Neklyudov , Sungsoo Ahn

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

We introduce RNA-FrameFlow, the first generative model for 3D RNA backbone design. We build upon SE(3) flow matching for protein backbone generation and establish protocols for data preparation and evaluation to address unique challenges…

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