{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T12:29:02Z","timestamp":1775219342471,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010006","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1715591"],"award-info":[{"award-number":["1715591"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000936","name":"Gordon and Betty Moore Foundation","doi-asserted-by":"publisher","award":["8415"],"award-info":[{"award-number":["8415"]}],"id":[{"id":"10.13039\/100000936","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["GCR-1934848"],"award-info":[{"award-number":["GCR-1934848"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM-139504-01"],"award-info":[{"award-number":["GM-139504-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of\n                    <jats:italic>\u03b2-Glucocerebrosidase<\/jats:italic>\n                    (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010006","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T14:11:45Z","timestamp":1649340705000},"page":"e1010006","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":37,"title":["Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2194-5199","authenticated-orcid":true,"given":"Nicholas J.","family":"Ose","sequence":"first","affiliation":[]},{"given":"Brandon M.","family":"Butler","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9911-3640","authenticated-orcid":true,"given":"Avishek","family":"Kumar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2593-4179","authenticated-orcid":true,"given":"I. Can","family":"Kazan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-9952","authenticated-orcid":true,"given":"Maxwell","family":"Sanderford","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-8212","authenticated-orcid":true,"given":"Sudhir","family":"Kumar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9351-3758","authenticated-orcid":true,"given":"S. Banu","family":"Ozkan","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"pcbi.1010006.ref001","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1146\/annurev.bi.58.070189.004001","article-title":"Mutational effects on protein stability","volume":"58","author":"T. Alber","year":"1989","journal-title":"Annu Rev Biochem"},{"key":"pcbi.1010006.ref002","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0022-2836(02)00442-4","article-title":"Predicting changes in the stability of proteins and protein complexes: A study of more than 1000 mutations","volume":"320","author":"R. Guerois","year":"2002","journal-title":"J Mol Biol"},{"key":"pcbi.1010006.ref003","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.jmb.2005.08.020","article-title":"Loss of protein structure stability as a major causative factor in monogenic disease","volume":"353","author":"P. Yue","year":"2005","journal-title":"J Mol Biol"},{"key":"pcbi.1010006.ref004","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.cell.2015.04.013","article-title":"Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders","volume":"161","author":"N Sahni","year":"2015","journal-title":"Cell"},{"key":"pcbi.1010006.ref005","doi-asserted-by":"crossref","DOI":"10.1016\/j.tig.2011.06.004","article-title":"Phylomedicine: an evolutionary telescope to explore and diagnose the universe of disease mutations","volume":"27","author":"S. Kumar","year":"2011","journal-title":"Trends Genet"},{"key":"pcbi.1010006.ref006","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/prot.24748","article-title":"Conformational dynamics of nonsynonymous variants at protein interfaces reveals disease association","volume":"83","author":"B.M. Butler","year":"2015","journal-title":"Proteins"},{"key":"pcbi.1010006.ref007","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nbt.2106","article-title":"Three-dimensional reconstruction of protein networks provides insight into human genetic disease","volume":"30","author":"X. Wang","year":"2012","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010006.ref008","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1158\/1078-0432.CCR-09-0070","article-title":"Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer","volume":"15","author":"S Krishnaswamy","year":"2009","journal-title":"Clin Cancer Res"},{"key":"pcbi.1010006.ref009","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/molbev\/msaa202","article-title":"Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions","volume":"38","author":"P Campitelli","year":"2020b","journal-title":"Mol Biol Evol"},{"key":"pcbi.1010006.ref010","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1002428","article-title":"Collective Dynamics Differentiates Functional Divergence in Protein Evolution","volume":"8","author":"T. Glembo","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010006.ref011","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1101\/gr.091991.109","article-title":"Positional conservation and amino acids shape the correct diagnosis and population frequencies of benign and damaging personal amino acid mutations","volume":"19","author":"S. Kumar","year":"2009","journal-title":"Genome Res"},{"key":"pcbi.1010006.ref012","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.sbi.2015.11.002","article-title":"Integration of structural dynamics and molecular evolution via protein interaction networks: a new era in genomic medicine","volume":"35","author":"A. Kumar","year":"2015a","journal-title":"Curr Opin Struct Biol"},{"key":"pcbi.1010006.ref013","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cell.2013.03.034","article-title":"Allostery in disease and in drug discovery","volume":"153","author":"R. Nussinov","year":"2013","journal-title":"Cell"},{"key":"pcbi.1010006.ref014","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bpj.2016.05.030","article-title":"Using Evolution to Guide Protein Engineering: The Devil IS in the Details","volume":"111","author":"L. Swint-Kruse","year":"2016","journal-title":"Biophys J"},{"key":"pcbi.1010006.ref015","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/nmeth.2147","article-title":"Evolutionary diagnosis method for variants in personal exomes","volume":"9","author":"S Kumar","year":"2012","journal-title":"Nat Methods"},{"key":"pcbi.1010006.ref016","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/humu.10212","article-title":"Human Gene Mutation Database (HGMD): 2003 update: HGMD 2003 UPDATE","volume":"21","author":"PD Stenson","year":"2003","journal-title":"Hum Mutat"},{"key":"pcbi.1010006.ref017","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/nsmb.2676","article-title":"Divergent evolution of protein conformational dynamics in dihydrofolate reductase","volume":"20","author":"G. Bhabha","year":"2013","journal-title":"Nat Struct Mol Biol"},{"key":"pcbi.1010006.ref018","article-title":"The role of protein dynamics in the evolution of new enzyme function","author":"E. Campbell","year":"2016","journal-title":"Nat Chem Biol"},{"key":"pcbi.1010006.ref019","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.str.2014.11.011","article-title":"A hinge migration mechanism unlocks the evolution of green-to-red photoconversion in GFP-like proteins","volume":"23","author":"H. Kim","year":"2015","journal-title":"Structure"},{"key":"pcbi.1010006.ref020","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1093\/molbev\/msu281","article-title":"Evolution of Conformational Dynamics Determines the Conversion of a Promiscuous Generalist into a Specialist Enzyme","volume":"32","author":"T. Zou","year":"2015","journal-title":"Mol Biol Evol"},{"key":"pcbi.1010006.ref021","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1098\/rstb.2017.0184","article-title":"Ancient thioredoxins evolved to modern-day stability\u2013function requirement by altering native state ensemble","volume":"373","author":"T Modi","year":"2018","journal-title":"Phil Trans R Soc B"},{"key":"pcbi.1010006.ref022","article-title":"Enzyme surface rigidity tunes the temperature dependence of catalytic rates","volume":"113","author":"G. Villy Isaksen","year":"2016","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010006.ref023","doi-asserted-by":"crossref","first-page":"5086","DOI":"10.1073\/pnas.1818411116","article-title":"Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning","volume":"116","author":"R Romero","year":"2019","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010006.ref024","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1038\/s41467-021-22089-0","article-title":"Hinge-shift mechanism as a protein design principle for the evolution of \u03b2-lactamases from substrate promiscuity to specificity","volume":"12","author":"T Modi","year":"2021","journal-title":"Nat Commun"},{"key":"pcbi.1010006.ref025","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1146\/annurev-biophys-052118-115517","article-title":"The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution","volume":"49","author":"P Campitelli","year":"2020a","journal-title":"Annu Rev Biophys"},{"key":"pcbi.1010006.ref026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4061\/2011\/973231","article-title":"A Guided Tour of the Structural Biology of Gaucher Disease: Acid- \u03b2 -Glucosidase and Saposin C","volume":"2011","author":"R.L. Lieberman","year":"2011","journal-title":"Enzyme Res"},{"key":"pcbi.1010006.ref027","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1056\/NEJMoa033277","article-title":"Mutations in the Glucocerebrosidase Gene and Parkinson\u2019s Disease in Ashkenazi Jews","volume":"351","author":"J Aharon-Peretz","year":"2004","journal-title":"N Engl J Med"},{"key":"pcbi.1010006.ref028","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13024-019-0336-2","article-title":"Glucocerebrosidase and its relevance to Parkinson disease","volume":"14","author":"J Do","year":"2019","journal-title":"Mol Neurodegener"},{"key":"pcbi.1010006.ref029","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1212\/01.wnl.0000276989.17578.02","article-title":"Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease","volume":"69","author":"LN Clark","year":"2007","journal-title":"Neurology"},{"key":"pcbi.1010006.ref030","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s11910-010-0102-x","article-title":"The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders","volume":"10","author":"A Velayati","year":"2010","journal-title":"Curr Neurol Neurosci Rep"},{"key":"pcbi.1010006.ref031","doi-asserted-by":"crossref","DOI":"10.1001\/archneurol.2009.54","article-title":"Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies","volume":"66","author":"LN Clark","year":"2009","journal-title":"Arch Neurol"},{"key":"pcbi.1010006.ref032","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nchembio850","article-title":"Structure of acid \u03b2-glucosidase with pharmacological chaperone provides insight into Gaucher disease","volume":"3","author":"R.L. Lieberman","year":"2007","journal-title":"Nat Chem Biol"},{"key":"pcbi.1010006.ref033","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/humu.20676","article-title":"Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)","volume":"29","author":"K.S. Hruska","year":"2008","journal-title":"Hum Mutat"},{"key":"pcbi.1010006.ref034","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/sj.embor.embor873","article-title":"X-ray structure of human acid-\u03b2-glucosidase, the defective enzyme in Gaucher disease","volume":"4","author":"H Dvir","year":"2003","journal-title":"EMBO Rep"},{"key":"pcbi.1010006.ref035","doi-asserted-by":"crossref","first-page":"4242","DOI":"10.1074\/jbc.M511110200","article-title":"Analyses of Variant Acid \u03b2-Glucosidases","volume":"281","author":"B Liou","year":"2006","journal-title":"J Biol Chem"},{"key":"pcbi.1010006.ref036","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.bpj.2015.06.060","article-title":"The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin","volume":"109","author":"A. Kumar","year":"2015b","journal-title":"Biophys J"},{"key":"pcbi.1010006.ref037","doi-asserted-by":"crossref","first-page":"6951","DOI":"10.1021\/acs.biochem.5b00635","article-title":"A Rigid Hinge Region Is Necessary for High-Affinity Binding of Dimannose to Cyanovirin and Associated Constructs","volume":"54","author":"Z. Li","year":"2015","journal-title":"Biochemistry"},{"key":"pcbi.1010006.ref038","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"I.A. Adzhubei","year":"2010","journal-title":"Nat Methods"},{"key":"pcbi.1010006.ref039","doi-asserted-by":"crossref","first-page":"e1006626","DOI":"10.1371\/journal.pcbi.1006626","article-title":"Coevolving residues inform protein dynamics profiles and disease susceptibility of nSNVs","volume":"14","author":"BM Butler","year":"2018","journal-title":"PLOS Comput Biol"},{"key":"pcbi.1010006.ref040","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1093\/bioinformatics\/btl423","article-title":"Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information","volume":"22","author":"E Capriotti","year":"2006","journal-title":"Bioinformatics"},{"key":"pcbi.1010006.ref041","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"H.M. Berman","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010006.ref042","first-page":"5.6.1","article-title":"Comparative Protein Structure Modeling Using Modeller","author":"Narayanan Eswar","year":"2014","journal-title":"Curr Protoc Bioinforma"},{"key":"pcbi.1010006.ref043","doi-asserted-by":"crossref","first-page":"667","DOI":"10.3390\/e22060667","article-title":"Allostery and Epistasis: Emergent Properties of Anisotropic Networks","volume":"22","author":"P Campitelli","year":"2020","journal-title":"Entropy"},{"key":"pcbi.1010006.ref044","article-title":"Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2","volume":"76","author":"I Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"pcbi.1010006.ref045","doi-asserted-by":"crossref","first-page":"e84598","DOI":"10.1371\/journal.pone.0084598","article-title":"Deriving a Mutation Index of Carcinogenicity Using Protein Structure and Protein Interfaces","volume":"9","author":"O Espinosa","year":"2014","journal-title":"PLoS ONE"},{"key":"pcbi.1010006.ref046","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/prot.24176","article-title":"Prediction of phenotypes of missense mutations in human proteins from biological assemblies: Missense Mutations and Biological Assemblies","volume":"81","author":"Q Wei","year":"2013","journal-title":"Proteins Struct Funct Bioinforma"},{"key":"pcbi.1010006.ref047","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1093\/bioinformatics\/btm119","article-title":"Finding new structural and sequence attributes to predict possible disease association of single amino acid polymorphism (SAP)","volume":"23","author":"Z-Q Ye","year":"2007","journal-title":"Bioinformatics"},{"key":"pcbi.1010006.ref048","doi-asserted-by":"crossref","first-page":"e1000135","DOI":"10.1371\/journal.pcbi.1000135","article-title":"Prediction by Graph Theoretic Measures of Structural Effects in Proteins Arising from Non-Synonymous Single Nucleotide Polymorphisms","volume":"4","author":"TMK Cheng","year":"2008","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010006.ref049","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/eva.12052","article-title":"Structural dynamics flexibility informs function and evolution at a proteome scale","volume":"6","author":"Z Nevin Gerek","year":"2013","journal-title":"Evol Appl"},{"key":"pcbi.1010006.ref050","doi-asserted-by":"crossref","first-page":"4164","DOI":"10.1073\/pnas.1715896115","article-title":"Structural dynamics is a determinant of the functional significance of missense variants","volume":"115","author":"L Ponzoni","year":"2018","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1010006.ref051","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1093\/bioinformatics\/btaa127","article-title":"Rhapsody: predicting the pathogenicity of human missense variants","volume":"36","author":"L Ponzoni","year":"2020","journal-title":"Bioinformatics"},{"key":"pcbi.1010006.ref052","article-title":"Allostery: An Overview of Its History, Concepts, Methods, and Applications","volume":"12","author":"J. Liu","year":"2016","journal-title":"PLOS Comput Biol"},{"key":"pcbi.1010006.ref053","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41929-019-0385-5","article-title":"Engineering new catalytic activities in enzymes","volume":"3","author":"K Chen","year":"2020","journal-title":"Nat Catal"},{"key":"pcbi.1010006.ref054","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1042\/BST20180614","article-title":"Protein engineering: the potential of remote mutations","volume":"47","author":"M Wilding","year":"2019","journal-title":"Biochem Soc Trans"},{"key":"pcbi.1010006.ref055","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nchembio.1503","article-title":"The role of distant mutations and allosteric regulation on LovD active site dynamics","volume":"10","author":"G Jim\u00e9nez-Os\u00e9s","year":"2014","journal-title":"Nat Chem Biol"},{"key":"pcbi.1010006.ref056","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/s41586-018-0183-2","article-title":"Dynamic allostery can drive cold adaptation in enzymes","volume":"558","author":"HG Saavedra","year":"2018","journal-title":"Nature"},{"key":"pcbi.1010006.ref057","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.3390\/ijms19123808","article-title":"Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 \u03b2-lactamase","volume":"19","author":"T Modi","year":"2018","journal-title":"Int J Mol Sci"},{"key":"pcbi.1010006.ref058","doi-asserted-by":"crossref","first-page":"D485","DOI":"10.1093\/nar\/gkt1243","article-title":"The Catalytic Site Atlas 2.0: cataloging catalytic sites and residues identified in enzymes","volume":"42","author":"N. Furnham","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010006.ref059","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000544","article-title":"Perturbation-response scanning reveals ligand entry-exit mechanisms of ferric binding protein","volume":"5","author":"C. Atilgan","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010006.ref060","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0006-3495(01)76033-X","article-title":"Anisotropy of fluctuation dynamics of proteins with an elastic network model","volume":"80","author":"A.R. Atilgan","year":"2001","journal-title":"Biophys J"},{"key":"pcbi.1010006.ref061","unstructured":"Schrodinger. The PyMOL Molecular Graphics System, Version 2.0.4. 2015."},{"key":"pcbi.1010006.ref062","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"JA Maier","year":"2015","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1010006.ref063","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/jcc.540160910","article-title":"Hydrophobic solvation of methane and nonbond parameters of the TIP3P water model","volume":"16","author":"Y. Sun","year":"1995","journal-title":"J Comput Chem"},{"key":"pcbi.1010006.ref064","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0010-4655(95)00041-D","article-title":"AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules","volume":"91","author":"D.A. Pearlman","year":"1995","journal-title":"Comput Phys Commun"},{"key":"pcbi.1010006.ref065","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1021\/ct400314y","article-title":"Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald","volume":"9","author":"R. Salomon-Ferrer","year":"2013","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1010006.ref066","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N \u00b7log (N) method for Ewald sums in large systems","volume":"98","author":"T Darden","year":"1993","journal-title":"J Chem Phys"},{"key":"pcbi.1010006.ref067","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"U Essmann","year":"1995","journal-title":"J Chem Phys"},{"key":"pcbi.1010006.ref068","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1021\/acs.jctc.5b00999","article-title":"Convergence of Molecular Dynamics Simulation of Protein Native States: Feasibility vs Self-Consistency Dilemma","volume":"12","author":"L Sawle","year":"2016","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1010006.ref069","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/BF01890115","article-title":"Efficient algorithms for agglomerative hierarchical clustering methods","volume":"1","author":"WHE Day","year":"1984","journal-title":"J Classif"},{"key":"pcbi.1010006.ref070","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/pro.3779","article-title":"ConSurf-DB: An accessible repository for the evolutionary conservation patterns of the majority of PDB proteins","volume":"29","author":"A Ben Chorin","year":"2020","journal-title":"Protein Sci"},{"key":"pcbi.1010006.ref071","doi-asserted-by":"crossref","first-page":"D323","DOI":"10.1093\/nar\/gkn822","article-title":"The ConSurf-DB: pre-calculated evolutionary conservation profiles of protein structures","volume":"37","author":"O Goldenberg","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010006.ref072","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/molbev\/msy096","article-title":"MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms","volume":"35","author":"S Kumar","year":"2018","journal-title":"Mol Biol Evol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010006","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T13:41:14Z","timestamp":1650375674000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010006"}},"subtitle":[],"editor":[{"given":"Anders","family":"Wallqvist","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,4,7]]},"references-count":72,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010006","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.09.24.461738","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,7]]}}}