{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T04:12:29Z","timestamp":1770696749628,"version":"3.49.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"vor","delay-in-days":3109,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/2.0\/uk\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: The ability of human immunodeficiency virus-1 (HIV-1) protease to develop mutations that confer multi-drug resistance (MDR) has been a major obstacle in designing rational therapies against HIV. Resistance is usually imparted by a cooperative mechanism that can be elucidated by a covariance analysis of sequence data. Identification of such correlated substitutions of amino acids may be obscured by evolutionary noise.<\/jats:p>\n               <jats:p>Results: HIV-1 protease sequences from patients subjected to different specific treatments (set 1), and from untreated patients (set 2) were subjected to sequence covariance analysis by evaluating the mutual information (MI) between all residue pairs. Spectral clustering of the resulting covariance matrices disclosed two distinctive clusters of correlated residues: the first, observed in set 1 but absent in set 2, contained residues involved in MDR acquisition; and the second, included those residues differentiated in the various HIV-1 protease subtypes, shortly referred to as the phylogenetic cluster. The MDR cluster occupies sites close to the central symmetry axis of the enzyme, which overlap with the global hinge region identified from coarse-grained normal-mode analysis of the enzyme structure. The phylogenetic cluster, on the other hand, occupies solvent-exposed and highly mobile regions. This study demonstrates (i) the possibility of distinguishing between the correlated substitutions resulting from neutral mutations and those induced by MDR upon appropriate clustering analysis of sequence covariance data and (ii) a connection between global dynamics and functional substitution of amino acids.<\/jats:p>\n               <jats:p>Contact: \u00a0bahar@ccbb.pitt.edu<\/jats:p>\n               <jats:p>Supplementary information: Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btn110","type":"journal-article","created":{"date-parts":[[2008,3,30]],"date-time":"2008-03-30T00:24:46Z","timestamp":1206836686000},"page":"1243-1250","source":"Crossref","is-referenced-by-count":31,"title":["Analysis of correlated mutations in HIV-1 protease using spectral clustering"],"prefix":"10.1093","volume":"24","author":[{"given":"Ying","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Computational Biology, School of Medicine, University of Pittsburgh, PA 15232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eran","family":"Eyal","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, School of Medicine, University of Pittsburgh, PA 15232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivet","family":"Bahar","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, School of Medicine, University of Pittsburgh, PA 15232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2008,3,28]]},"reference":[{"key":"2023020210054664600_B1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1093\/oxfordjournals.molbev.a026229","article-title":"Correlations among amino acid sites in bHLH protein domains: an information theoretic analysis","volume":"17","author":"Atchley","year":"2000","journal-title":"Mol. Biol. Evol"},{"key":"2023020210054664600_B2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1359-0278(97)00024-2","article-title":"Direct evaluation of thermal fluctuations in protein using a single parameter harmonic potential","volume":"2","author":"Bahar","year":"1997","journal-title":"Fold. Des"},{"key":"2023020210054664600_B3","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1103\/PhysRevLett.80.2733","article-title":"Vibrational dynamics of proteins: significance of slow and fast modes in relation to function and stability","volume":"80","author":"Bahar","year":"1998","journal-title":"Phys. Rev. lett"},{"key":"2023020210054664600_B4","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/prot.1049","article-title":"Molecular dynamics studies on HIV-1 protease drug resistance and folding pathways","volume":"43","author":"Cecconi","year":"2001","journal-title":"Proteins"},{"key":"2023020210054664600_B5","doi-asserted-by":"crossref","first-page":"18184","DOI":"10.1074\/jbc.M600349200","article-title":"Evolutionarily conserved allosteric network in the Cys loop family of ligand-gated ion channels revealed by statistical covariance analyses","volume":"281","author":"Chen","year":"2006","journal-title":"J. Biol. Chem"},{"key":"2023020210054664600_B6","volume-title":"Spectral Graph Theory","author":"Chung","year":"1997"},{"key":"2023020210054664600_B7","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1002\/pro.5560041104","article-title":"Covariation of residues in the homeodomain sequence family","volume":"4","author":"Clarke","year":"1995","journal-title":"Protein Sci"},{"key":"2023020210054664600_B8","doi-asserted-by":"crossref","DOI":"10.1002\/0471200611","volume-title":"Elements of Information Theory","author":"Cover","year":"1991"},{"key":"2023020210054664600_B9","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/prot.21223","article-title":"A pair-to-pair amino acids substitution matrix and its applications for protein structure prediction","volume":"67","author":"Eyal","year":"2007","journal-title":"Proteins"},{"key":"2023020210054664600_B10","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1093\/bioinformatics\/btm256","article-title":"Rapid assessment of correlated amino acids from pair-to-pair (P2P) substitution matrices","volume":"23","author":"Eyal","year":"2007","journal-title":"Bioinformatics"},{"key":"2023020210054664600_B11","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jmb.2004.04.064","article-title":"An evolutionarily conserved network of amino acids mediates gating in voltage-dependent potassium channels","volume":"340","author":"Fleishman","year":"2001","journal-title":"J. Mol. Biol"},{"key":"2023020210054664600_B12","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/prot.20098","article-title":"Influence of conservation on calculations of amino acid covariance in multiple sequence alignments","volume":"56","author":"Fodor","year":"2004","journal-title":"Proteins"},{"key":"2023020210054664600_B13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/prot.340180402","article-title":"Correlated mutations and residue contacts in proteins","volume":"18","author":"Gobel","year":"1994","journal-title":"Proteins"},{"key":"2023020210054664600_B14","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1086\/323601","article-title":"Human immunodeficiency virus type 1 reverse-transcriptase and protease subtypes: classification, amino acid mutation patterns, and prevalence in a northern California clinic-based population","volume":"184","author":"Gonzales","year":"2001","journal-title":"J. Infect. Dis"},{"key":"2023020210054664600_B15","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1103\/PhysRevLett.79.3090","article-title":"Gaussian dynamics of folded protein","volume":"79","author":"Haliloglu","year":"1997","journal-title":"Phys. Rev. Lett"},{"key":"2023020210054664600_B16","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1002\/prot.20933","article-title":"Correlated mutations: advances and limitations. A study on fusion proteins and on the Cohesin-Dockerin families","volume":"63","author":"Halperin","year":"2006","journal-title":"Proteins"},{"key":"2023020210054664600_B17","first-page":"33","article-title":"Allosteric determinants in guanine nucleotide-binding proteins","volume":"99","author":"Hatley","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210054664600_B18","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1097\/00002030-200006160-00018","article-title":"Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross resistance: a survey of over 6000 samples","volume":"14","author":"Hertogs","year":"2000","journal-title":"AIDS"},{"key":"2023020210054664600_B19","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/S0042-6822(03)00484-7","article-title":"Covariation of amino acid positions in HIV-1 protease","volume":"314","author":"Hoffman","year":"2003","journal-title":"Virology"},{"key":"2023020210054664600_B20","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1073\/pnas.0508452103","article-title":"HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations","volume":"103","author":"Hornak","year":"2006","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210054664600_B21","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/prot.10180","article-title":"Mapping pathways of allosteric communication in GroEL by analysis of correlated mutations","volume":"48","author":"Kass","year":"2002","journal-title":"Proteins"},{"key":"2023020210054664600_B22","doi-asserted-by":"crossref","first-page":"e112","DOI":"10.1371\/journal.pmed.0020112","article-title":"Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration","volume":"2","author":"Kantor","year":"2005","journal-title":"PLoS Med"},{"key":"2023020210054664600_B23","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1089\/aid.1992.8.1549","article-title":"Signature pattern analysis: a method for assessing viral sequence relatedness","volume":"8","author":"Korber","year":"1992","journal-title":"AIDS Res. Hum. Retro"},{"key":"2023020210054664600_B24","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1089\/108729104323038874","article-title":"Cross-resistance patterns among HIV protease inhibitors","volume":"18","author":"Kozal","year":"2004","journal-title":"AIDS Patient Care STDs"},{"key":"2023020210054664600_B25","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1126\/science.286.5438.295","article-title":"Evolutionarily conserved pathways of energetic connectivity in protein families","volume":"286","author":"Lockless","year":"1999","journal-title":"Science"},{"key":"2023020210054664600_B26","doi-asserted-by":"crossref","first-page":"4116","DOI":"10.1093\/bioinformatics\/bti671","article-title":"Using information theory to search for co-evolving residues in proteins","volume":"21","author":"Martin","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020210054664600_B27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/protein\/gzi029","article-title":"Detection and reduction of evolutionary noise in correlated mutation analysis","volume":"18","author":"Noivirt","year":"2005","journal-title":"Protein Eng. Des. Sel"},{"key":"2023020210054664600_B28","doi-asserted-by":"crossref","first-page":"13659","DOI":"10.1021\/bi0350405","article-title":"Multidrug resistance to HIV-1 protease inhibition requires cooperative coupling between distal mutations","volume":"42","author":"Ohtaka","year":"2003","journal-title":"Biochemistry"},{"key":"2023020210054664600_B29","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1006\/jmbi.1999.3208","article-title":"Effective use of sequence correlation and conservation in fold recognition","volume":"293","author":"Olmea","year":"1999","journal-title":"J. Mol. Biol"},{"key":"2023020210054664600_B30","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1110\/ps.03468904","article-title":"HIV-1 protease molecular dynamics of a wild-type and of the V82F\/I84V mutant: Possible contributions to drug resistance and a potential new target site for drugs","volume":"13","author":"Perryman","year":"2004","journal-title":"Protein Sci"},{"key":"2023020210054664600_B31","doi-asserted-by":"crossref","first-page":"12446","DOI":"10.1128\/JVI.78.22.12446-12454.2004","article-title":"Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease","volume":"78","author":"Prabu-Jeyabalan","year":"2004","journal-title":"J. Virol"},{"key":"2023020210054664600_B32","first-page":"41","article-title":"The Gaussian Network Model: Theory and Applications","volume-title":"Normal Mode Analysis. Theory and Applications to Biological and Chemical Systems","author":"Rader","year":"2006"},{"key":"2023020210054664600_B33","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1093\/nar\/gkg100","article-title":"Human immunodeficiency virus reverse transcriptase and protease sequence database","volume":"31","author":"Rhee","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"2023020210054664600_B34","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/prot.21791","article-title":"Contact prediction using mutual information and neural nets","volume":"69","author":"Shackelford","year":"2007","journal-title":"Proteins"},{"key":"2023020210054664600_B35","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1128\/CMR.15.2.247-277.2002","article-title":"Genotypic testing for human immunodeficiency virus type 1 drug resistance","volume":"15","author":"Shafer","year":"2002","journal-title":"Clin. Microbiol. Rev"},{"key":"2023020210054664600_B36","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1109\/34.868688","article-title":"Normalized cut and image segmentation","volume":"22","author":"Shi","year":"2000","journal-title":"IEEE Tran. Pattern Anal. Mach. Intell"},{"key":"2023020210054664600_B37","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/protein\/7.3.349","article-title":"Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?","volume":"7","author":"Shindyalov","year":"1994","journal-title":"Protein Eng"},{"key":"2023020210054664600_B38","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0092-8674(04)00119-9","article-title":"Structural determinants of allosteric ligand activation in RXR Heterodimers","volume":"116","author":"Shulman","year":"2004","journal-title":"Cell"},{"key":"2023020210054664600_B39","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nsb881","article-title":"Evolutionarily conserved networks of residues mediate allosteric communication in proteins","volume":"10","author":"S\u00fcel","year":"2003","journal-title":"Nat. Struct. Biol"},{"key":"2023020210054664600_B40","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1093\/protein\/9.11.941","article-title":"The prediction of protein contacts from multiple sequence alignments","volume":"9","author":"Thomas","year":"1996","journal-title":"Protein Eng"},{"key":"2023020210054664600_B41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0169-7439(87)80084-9","article-title":"Principal component analysis","volume":"2","author":"Wold","year":"1987","journal-title":"Chemometr. Intell. Lab. Syst"},{"key":"2023020210054664600_B42","doi-asserted-by":"crossref","first-page":"4836","DOI":"10.1128\/JVI.77.8.4836-4847.2003","article-title":"Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments","volume":"77","author":"Wu","year":"2003","journal-title":"J. Virol"},{"key":"2023020210054664600_B43","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.str.2005.03.015","article-title":"Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes","volume":"13","author":"Yang","year":"2005","journal-title":"Structure"},{"key":"2023020210054664600_B44","doi-asserted-by":"crossref","first-page":"W24","DOI":"10.1093\/nar\/gkl084","article-title":"oGNM: online computation of structural dynamics using the Gaussian Network Model","volume":"34","author":"Yang","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2023020210054664600_B45","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1006\/jmbi.2001.5173","article-title":"Relation between sequence and structure of HIV-1 protease inhibitor complexes: a model system for the analysis of protein flexibility","volume":"315","author":"Zoete","year":"2002","journal-title":"J. Mol. Biol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/10\/1243\/49047928\/bioinformatics_24_10_1243.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/10\/1243\/49047928\/bioinformatics_24_10_1243.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T11:43:07Z","timestamp":1675338187000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/24\/10\/1243\/177710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,3,28]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2008,5,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btn110","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,5,15]]},"published":{"date-parts":[[2008,3,28]]}}}