{"title":"通过化学精确接触反应分析(ChACRA)揭示蛋白质异位。","authors":"Daniel Burns, Vincenzo Venditti, Davit A Potoyan","doi":"10.1021/acs.jctc.4c00414","DOIUrl":null,"url":null,"abstract":"<p><p>Decoding allostery at the atomic level is essential for understanding the relationship between a protein's sequence, structure, and dynamics. Recently, we have shown that decomposing temperature responses of inter-residue contacts can reveal allosteric couplings and provide useful insight into the functional dynamics of proteins. The details of this Chemically Accurate Contact Response Analysis (ChACRA) are presented here along with its application to two well-known allosteric proteins. The first protein, IGPS, is a model of ensemble allostery that lacks clear structural differences between the active and inactive states. We show that the application of ChACRA reveals the experimentally identified allosteric coupling between effector and active sites of IGPS. The second protein, ATCase, is a classic example of allostery with distinct active and inactive structural states. Using ChACRA, we directly identify the most significant residue level interactions underlying the enzyme's cooperative behavior. Both test cases demonstrate the utility of ChACRA's unsupervised machine learning approach for dissecting allostery at the residue level.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Illuminating Protein Allostery by Chemically Accurate Contact Response Analysis (ChACRA).\",\"authors\":\"Daniel Burns, Vincenzo Venditti, Davit A Potoyan\",\"doi\":\"10.1021/acs.jctc.4c00414\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Decoding allostery at the atomic level is essential for understanding the relationship between a protein's sequence, structure, and dynamics. Recently, we have shown that decomposing temperature responses of inter-residue contacts can reveal allosteric couplings and provide useful insight into the functional dynamics of proteins. The details of this Chemically Accurate Contact Response Analysis (ChACRA) are presented here along with its application to two well-known allosteric proteins. The first protein, IGPS, is a model of ensemble allostery that lacks clear structural differences between the active and inactive states. We show that the application of ChACRA reveals the experimentally identified allosteric coupling between effector and active sites of IGPS. The second protein, ATCase, is a classic example of allostery with distinct active and inactive structural states. Using ChACRA, we directly identify the most significant residue level interactions underlying the enzyme's cooperative behavior. Both test cases demonstrate the utility of ChACRA's unsupervised machine learning approach for dissecting allostery at the residue level.</p>\",\"PeriodicalId\":45,\"journal\":{\"name\":\"Journal of Chemical Theory and Computation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Theory and Computation\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jctc.4c00414\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/22 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Theory and Computation","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/acs.jctc.4c00414","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Illuminating Protein Allostery by Chemically Accurate Contact Response Analysis (ChACRA).
Decoding allostery at the atomic level is essential for understanding the relationship between a protein's sequence, structure, and dynamics. Recently, we have shown that decomposing temperature responses of inter-residue contacts can reveal allosteric couplings and provide useful insight into the functional dynamics of proteins. The details of this Chemically Accurate Contact Response Analysis (ChACRA) are presented here along with its application to two well-known allosteric proteins. The first protein, IGPS, is a model of ensemble allostery that lacks clear structural differences between the active and inactive states. We show that the application of ChACRA reveals the experimentally identified allosteric coupling between effector and active sites of IGPS. The second protein, ATCase, is a classic example of allostery with distinct active and inactive structural states. Using ChACRA, we directly identify the most significant residue level interactions underlying the enzyme's cooperative behavior. Both test cases demonstrate the utility of ChACRA's unsupervised machine learning approach for dissecting allostery at the residue level.
期刊介绍:
The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.