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The evolutionary trajectory of a protein through sequence space is constrained by function and three-dimensional (3D) structure. Residues in spatial proximity tend to co-evolve, yet attempts to invert the evolutionary record to identify…

Biomolecules · Quantitative Biology 2015-03-13 Debora S. Marks , Lucy J. Colwell , Robert Sheridan , Thomas A. Hopf , Andrea Pagnani , Riccardo Zecchina , Chris Sander

Predicting ATP-Protein Binding sites in genes is of great significance in the field of Biology and Medicine. The majority of research in this field has been conducted through time- and resource-intensive 'wet experiments' in laboratories.…

Biomolecules · Quantitative Biology 2024-02-06 Shreyas V , Swati Agarwal

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how…

Machine Learning · Computer Science 2022-06-29 Erik Nijkamp , Jeffrey Ruffolo , Eli N. Weinstein , Nikhil Naik , Ali Madani

Recent advances in de novo protein binder design have enabled increasing experimental validation, yet reported in silico metrics remain difficult to interpret or compare across studies due to non-standardized evaluation protocols. We…

Quantitative Methods · Quantitative Biology 2026-05-25 Cong Liu , Milong Ren , Jiaqi Guan , Chengyue Gong , Jinyuan Sun , Xinshi Chen , Wenzhi Xiao

Structure determination is key to understanding protein function at a molecular level. Whilst significant advances have been made in predicting structure and function from amino acid sequence, researchers must still rely on expensive,…

Computer Vision and Pattern Recognition · Computer Science 2020-09-01 Alexander Hudson , Shaogang Gong

Natural protein sequences somehow encode the structural forms that these molecules adopt. Recent developments in structure-prediction are agnostic to the mechanisms by which proteins fold and represent them as static objects. However, the…

Biomolecules · Quantitative Biology 2025-05-26 Ezequiel A. Galpern , Federico Caamaño , Diego U. Ferreiro

Motivation: Protein-ligand affinity prediction is an important part of structure-based drug design. It includes molecular docking and affinity prediction. Although molecular dynamics can predict affinity with high accuracy at present, it is…

Biomolecules · Quantitative Biology 2021-05-12 Yeji Wang , Shuo Wu , Yanwen Duan , Yong Huang

The majority of machine learning scoring functions used in drug discovery for predicting protein-ligand binding poses and affinities have been trained on the PDBBind dataset. However, it is unclear whether these new scoring functions are…

Biological Physics · Physics 2026-01-13 Jie Li , Xingyi Guan , Oufan Zhang , Kunyang Sun , Yingze Wang , Dorian Bagni , Teresa Head-Gordon

Accurate prediction of protein-ligand binding affinities is an essential challenge in structure-based drug design. Despite recent advances in data-driven methods for affinity prediction, their accuracy is still limited, partially because…

Biomolecules · Quantitative Biology 2024-09-04 Yaosen Min , Ye Wei , Peizhuo Wang , Xiaoting Wang , Han Li , Nian Wu , Stefan Bauer , Shuxin Zheng , Yu Shi , Yingheng Wang , Ji Wu , Dan Zhao , Jianyang Zeng

Despite the importance of a thermodynamically stable structure with a conserved fold for protein function, almost all evolutionary models neglect site-site correlations that arise from physical interactions between neighboring amino acid…

Populations and Evolution · Quantitative Biology 2013-12-04 Andrew J. Bordner , Hans D. Mittelmann

Current protein language models (pLMs) predominantly focus on single-chain protein sequences and often have not accounted for constraints on generative design imposed by protein-protein interactions. To address this gap, we present paired…

Biomolecules · Quantitative Biology 2023-11-22 Simon K. S. Chu , Kathy Y. Wei

Figuring out small molecule binding sites in target proteins, in the resolution of either pocket or residue, is critical in many virtual and real drug-discovery scenarios. Since it is not always easy to find such binding sites based on…

Quantitative Methods · Quantitative Biology 2023-04-19 Daeseok Lee , Jeunghyun Byun , Bonggun Shin

Accurately assigning folds for divergent protein sequences is a major obstacle to structural studies and underlies the inverse protein folding problem. Herein, we outline our theories for fold-recognition in the "twilight-zone" of sequence…

Quantitative Methods · Quantitative Biology 2010-08-31 Yoojin Hong , Kyung Dae Ko , Gaurav Bhardwaj , Zhenhai Zhang , Damian B. van Rossum , Randen L. Patterson

Protein sequence design must balance designability, defined as the ability to recover a target backbone, with multiple, often competing, developability properties such as solubility, thermostability, and expression. Existing approaches…

Machine Learning · Computer Science 2026-03-11 Xiaoyang Hou , Junqi Liu , Chence Shi , Xin Liu , Zhi Yang , Jian Tang

In sequence-based predictions, conventionally an input sequence is represented by a multiple sequence alignment (MSA) or a representation derived from MSA, such as a position-specific scoring matrix. Recently, inspired by the development in…

Quantitative Methods · Quantitative Biology 2021-10-18 Nabil Ibtehaz , Daisuke Kihara

Protein-ligand complex structures have been utilised to design benchmark machine learning methods that perform important tasks related to drug design such as receptor binding site detection, small molecule docking and binding affinity…

Biomolecules · Quantitative Biology 2021-08-26 Rishal Aggarwal , Akash Gupta , U Deva Priyakumar

Prediction of protein-ligand interactions (PLI) plays a crucial role in drug discovery as it guides the identification and optimization of molecules that effectively bind to target proteins. Despite remarkable advances in deep…

Biomolecules · Quantitative Biology 2023-07-18 Seokhyun Moon , Sang-Yeon Hwang , Jaechang Lim , Woo Youn Kim

The capacity of proteins to interact specifically with one another underlies our conceptual understanding of how living systems function. Systems-level study of specificity in protein-protein interactions is complicated by the fact that the…

Biomolecules · Quantitative Biology 2009-11-13 Eric Deeds , orr Ashenberg , Jaline Gerardine , Eugene Shakhnovich

Deep learning has transformed protein design, enabling accurate structure prediction, sequence optimization, and de novo protein generation. Advances in single-chain protein structure prediction via AlphaFold2, RoseTTAFold, ESMFold, and…

Machine Learning · Computer Science 2025-02-27 Gregory W. Kyro , Tianyin Qiu , Victor S. Batista

The Basic Local Alignment Search Tool (BLAST) is currently the most popular method for searching databases of biological sequences. BLAST compares sequences via similarity defined by a weighted edit distance, which results in it being…

Biomolecules · Quantitative Biology 2020-10-29 Amir Shanehsazzadeh , David Belanger , David Dohan