Impact of dimerization and N3 binding on molecular dynamics of SARS-CoV and SARS-CoV-2 main proteases

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dc.authoridYildirim, Ahmet/0000-0003-1495-0288
dc.authoridTekpinar, Mustafa/0000-0002-0207-0446
dc.contributor.authorTekpinar, Mustafa
dc.contributor.authorYildirim, Ahmet
dc.date.accessioned2024-12-24T19:28:11Z
dc.date.available2024-12-24T19:28:11Z
dc.date.issued2022
dc.departmentSiirt Üniversitesi
dc.description.abstractSARS-CoV-2 main protease is one of the major targets in drug development efforts against Covid-19. Even though several structures were reported to date, its dynamics is not understood well. In particular, impact of dimerization and ligand binding on the dynamics is an important issue to investigate. In this study, we performed molecular dynamics simulations of SARS-CoV and SARS-CoV-2 main proteases to investigate influence of dimerization on the dynamics by modeling monomeric and dimeric apo and holo forms. The dimerization causes an organization of the interdomain dynamics as well as some local structural changes. Moreover, we investigated impact of a peptide mimetic (N3) on the dynamics of SARS-CoV and SARS-CoV-2 Mpro. The ligand binding to the dimeric forms causes some key local changes at the dimer interface and it causes an allosteric interaction between the active sites of two protomers. Our results support the idea that only one protomer is active on SARS-CoV-2 due to this allosteric interaction. Additionally, we analyzed the molecular dynamics trajectories from graph theoretical perspective and found that the most influential residues - as measured by eigenvector centrality - are a group of residues in active site and dimeric interface of the protease. This study may form a bridge between what we know about the dynamics of SARS-CoV and SARS-CoV-2 Mpro. We think that enlightening allosteric communication of the active sites and the role of dimerization in SARS-CoV-2 Mpro can contribute to development of novel drugs against this global health problem as well as other similar proteases. Communicated by Ramaswamy H. Sarma
dc.description.sponsorshipInvestissement d'Avenir grant [ANR-16-CONV-0005]; Programme PAUSE of College de France; Agence Nationale de la Recherche (ANR) [ANR-16-CONV-0005] Funding Source: Agence Nationale de la Recherche (ANR)
dc.description.sponsorshipThis work was granted access to the Jean-Zay HPC resources of IDRIS under the allocation 2020-AP010711656 made by GENCI. Also, we utilized GPU-based computing resources of Inception program (Investissement d'Avenir grant [grant no. ANR-16-CONV-0005]. MT thanks to Programme PAUSE of College de France for their support.
dc.identifier.doi10.1080/07391102.2021.1880481
dc.identifier.endpage6254
dc.identifier.issn0739-1102
dc.identifier.issn1538-0254
dc.identifier.issue14
dc.identifier.pmid33525993
dc.identifier.scopus2-s2.0-85100233625
dc.identifier.scopusqualityQ1
dc.identifier.startpage6243
dc.identifier.urihttps://doi.org/10.1080/07391102.2021.1880481
dc.identifier.urihttps://hdl.handle.net/20.500.12604/6940
dc.identifier.volume40
dc.identifier.wosWOS:000613832700001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherTaylor & Francis Inc
dc.relation.ispartofJournal of Biomolecular Structure & Dynamics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241222
dc.subjectAllostery
dc.subjectCovid-19
dc.subjectdimerization
dc.subjecteigenvector centrality
dc.subjectlinear mutual information
dc.subjectmain protease (3C-like protease)
dc.subjectmolecular dynamics
dc.subjectN3
dc.subjectSARS-CoV
dc.subjectSARS-CoV-2
dc.titleImpact of dimerization and N3 binding on molecular dynamics of SARS-CoV and SARS-CoV-2 main proteases
dc.typeArticle

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