Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniversidade Federal do ABC (UFABC)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorLBPA-
Autor(es): dc.creatorGasparini, P.-
Autor(es): dc.creatorPhilot, E. A.-
Autor(es): dc.creatorPantaleão, S. Q.-
Autor(es): dc.creatorTorres-Bonfim, N. E.S.M.-
Autor(es): dc.creatorKliousoff, A.-
Autor(es): dc.creatorQuiroz, R. C.N.-
Autor(es): dc.creatorPerahia, D.-
Autor(es): dc.creatorSimões, R. P.-
Autor(es): dc.creatorMagro, A. J.-
Autor(es): dc.creatorScott, A. L.-
Data de aceite: dc.date.accessioned2025-08-21T21:35:55Z-
Data de disponibilização: dc.date.available2025-08-21T21:35:55Z-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2023-07-29-
Data de envio: dc.date.issued2023-06-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.jmgm.2023.108443-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/246927-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/246927-
Descrição: dc.descriptionThe main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Several Mpro mutations were found in SARS-CoV-2 variants, which are related to higher transmissibility, pathogenicity, and resistance to neutralization antibodies. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. In this study, we used a hybrid simulation method to generate intermediate structures along the six lowest frequency normal modes and sample the conformational space and characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutations, including mutations found in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. We tried to contribute to the elucidation of the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro. A machine learning analysis was performed following the investigation regarding the influence of the K90R, P99L, P108S, and N151D mutations on the dimeric interface assembling of the SARS-CoV-2 Mpro. The parameters allowed the selection of potential structurally stable dimers, which demonstrated that some single surface aa substitutions not located at the dimeric interface (K90R, P99L, P108S, and N151D) are able to induce significant quaternary changes. Furthermore, our results demonstrated, by a Quantum Mechanics method, the influence of SARS-CoV-2 Mpro mutations on the catalytic mechanism, confirming that only one of the chains of the WT and mutant SARS-CoV-2 Mpros are prone to cleave substrates. Finally, it was also possible to identify the aa residue F140 as an important factor related to the increasing enzymatic reactivity of a significant number of SARS-CoV-2 Mpro conformations generated by the normal modes-based simulations.-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionUniversidade Estadual Paulista-
Descrição: dc.descriptionComputational Biology and Biophysics Laboratory Federal University of ABC - UFABC, Santo André-
Descrição: dc.descriptionDepartment of Bioprocesses and Biotechnology School of Agriculture (FCA) Unesp, Botucatu-
Descrição: dc.descriptionInstitute of Biotechnology (IBTEC) Unesp, Botucatu-
Descrição: dc.descriptionÉcole Normale Supérieure Paris-Saclay LBPA, Scaly-
Descrição: dc.descriptionDepartment of Bioprocesses and Biotechnology School of Agriculture (FCA) Unesp, Botucatu-
Descrição: dc.descriptionInstitute of Biotechnology (IBTEC) Unesp, Botucatu-
Descrição: dc.descriptionCNPq: 164052/2020-8-
Descrição: dc.descriptionCNPq: 423717/2021-9-
Idioma: dc.languageen-
Relação: dc.relationJournal of Molecular Graphics and Modelling-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectMain protease-
Palavras-chave: dc.subjectMolecular dynamics-
Palavras-chave: dc.subjectMutation-
Palavras-chave: dc.subjectNormal modes-
Palavras-chave: dc.subjectQuantum mechanics-
Palavras-chave: dc.subjectResidue F140-
Palavras-chave: dc.subjectSARS-CoV-2-
Palavras-chave: dc.subjectStructural dynamics-
Título: dc.titleUnveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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