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We propose a model that explains the hierarchical organization of proteins in fold families. The model, which is based on the evolutionary selection of proteins by their native state stability, reproduces patterns of amino acids conserved…

Statistical Mechanics · Physics 2007-05-23 Nikolay V. Dokholyan , Eugene I. Shakhnovich

Protein inverse folding aims to design an amino acid sequence that will fold into a given backbone structure, serving as a central task in protein design. Two main paradigms have been widely explored. Template-based methods exploit…

Machine Learning · Computer Science 2026-03-17 Yiran Zhu , Changxi Chi , Hongxin Xiang , Wenjie Du , Xiaoqi Wang , Jun Xia

Prediction of protein structures using computational approaches has been explored for over two decades, paving a way for more focused research and development of algorithms in comparative modelling, ab intio modelling and structure…

Quantitative Methods · Quantitative Biology 2020-05-19 Surbhi Dhingra , Ramanathan Sowdhamini , Frédéric Cadet , Bernard Offmann

Protein structure prediction has reached revolutionary levels of accuracy on single structures, yet distributional modeling paradigms are needed to capture the conformational ensembles and flexibility that underlie biological function.…

Biomolecules · Quantitative Biology 2023-04-06 Bowen Jing , Ezra Erives , Peter Pao-Huang , Gabriele Corso , Bonnie Berger , Tommi Jaakkola

De novo functional protein design aims to generate protein sequences that realize specified biochemical functions without relying on evolutionary templates, enabling broad applications in biotechnology and medicine. Existing approaches…

Quantitative Methods · Quantitative Biology 2026-05-05 Xinrui Chen , Yizhen Luo , Siqi Fan , Zaiqing Nie

Computational protein design has a wide variety of applications. Despite its remarkable success, designing a protein for a given structure and function is still a challenging task. On the other hand, the number of solved protein structures…

Quantitative Methods · Quantitative Biology 2018-04-26 Jingxue Wang , Huali Cao , John Z. H. Zhang , Yifei Qi

Understanding how proteins structurally interact is crucial to modern biology, with applications in drug discovery and protein design. Recent machine learning methods have formulated protein-small molecule docking as a generative problem…

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

It has recently been discovered that many biological systems, when represented as graphs, exhibit a scale-free topology. One such system is the set of structural relationships among protein domains. The scale-free nature of this and other…

Populations and Evolution · Quantitative Biology 2009-11-10 Eric J. Deeds , Eugene I. Shakhnovich

Proteins are dynamic molecular machines whose biological functions, spanning enzymatic catalysis, signal transduction, and structural adaptation, are intrinsically linked to their motions. Designing proteins with targeted dynamic…

Biomolecules · Quantitative Biology 2025-02-17 Bo Ni , Markus J. Buehler

Generating novel active molecules for a given protein is an extremely challenging task for generative models that requires an understanding of the complex physical interactions between the molecule and its environment. In this paper, we…

Protein binder design is central to therapeutics, diagnostics, and synthetic biology, yet practical deployment remains challenging due to fragmented workflows, high computational costs, and complex tool integration. We present…

Biomolecules · Quantitative Biology 2025-05-29 Jie Gao , Jun Li , Jing Hu , Shanzhuo Zhang , Kunrui Zhu , Yueyang Huang , Xiaonan Zhang , Xiaomin Fang

In this work, we introduce a method to fine-tune a Transformer-based generative model for molecular de novo design. Leveraging the superior sequence learning capacity of Transformers over Recurrent Neural Networks (RNNs), our model can…

Machine Learning · Computer Science 2024-03-11 Pengcheng Xu , Tao Feng , Tianfan Fu , Siddhartha Laghuvarapu , Jimeng Sun

Sampling useful three-dimensional molecular structures along with their most favorable conformations is a key challenge in drug discovery. Current state-of-the-art 3D de-novo design flow matching or diffusion-based models are limited to…

Machine Learning · Computer Science 2025-11-24 Riccardo Tedoldi , Ola Engkvist , Patrick Bryant , Hossein Azizpour , Jon Paul Janet , Alessandro Tibo

Highly accurate biomolecular structure prediction is a key component of developing biomolecular foundation models, and one of the most critical aspects of building foundation models is identifying the recipes for scaling the model. In this…

Biomolecules · Quantitative Biology 2026-01-02 Yi Zhou , Chan Lu , Yiming Ma , Wei Qu , Fei Ye , Kexin Zhang , Lan Wang , Minrui Gui , Quanquan Gu

Recent advances in coarse-grained lattice and off-lattice protein models are reviewed. The sequence dependence of thermodynamical folding properties are investigated and evidence for non-randomness of the binary sequences of good folders…

High Energy Physics - Lattice · Physics 2015-06-25 C. Peterson

We develop ProxelGen, a protein structure generative model that operates on 3D densities as opposed to the prevailing 3D point cloud representations. Representing proteins as voxelized densities, or proxels, enables new tasks and…

Biomolecules · Quantitative Biology 2025-06-25 Felix Faltings , Hannes Stark , Regina Barzilay , Tommi Jaakkola

Designing protein sequences with specific biological functions and structural stability is crucial in biology and chemistry. Generative models already demonstrated their capabilities for reliable protein design. However, previous models are…

Machine Learning · Computer Science 2024-02-28 Lin Zongying , Li Hao , Lv Liuzhenghao , Lin Bin , Zhang Junwu , Chen Calvin Yu-Chian , Yuan Li , Tian Yonghong

Designing new protein structures is fundamental to computational biology, enabling advances in therapeutic molecule discovery and enzyme engineering. Existing diffusion-based generative models typically operate in Cartesian coordinate…

Biomolecules · Quantitative Biology 2025-11-25 Lakshaditya Singh , Adwait Shelke , Divyansh Agrawal

Unlocking the next generation of biotechnology and therapeutic innovation demands overcoming the inherent complexity and resource-intensity of conventional protein engineering methods. Recent GenAI-powered computational techniques often…