Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.jmgm.2023.108443 http://hdl.handle.net/11449/246927 |
Resumo: | The 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. |
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Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methodsMain proteaseMolecular dynamicsMutationNormal modesQuantum mechanicsResidue F140SARS-CoV-2Structural dynamicsThe 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.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Estadual PaulistaComputational Biology and Biophysics Laboratory Federal University of ABC - UFABC, Santo AndréDepartment of Bioprocesses and Biotechnology School of Agriculture (FCA) Unesp, BotucatuInstitute of Biotechnology (IBTEC) Unesp, BotucatuÉcole Normale Supérieure Paris-Saclay LBPA, ScalyDepartment of Bioprocesses and Biotechnology School of Agriculture (FCA) Unesp, BotucatuInstitute of Biotechnology (IBTEC) Unesp, BotucatuCNPq: 164052/2020-8CNPq: 423717/2021-9Universidade Federal do ABC (UFABC)Universidade Estadual Paulista (UNESP)LBPAGasparini, P.Philot, E. A.Pantaleão, S. Q.Torres-Bonfim, N. E.S.M.Kliousoff, A.Quiroz, R. C.N.Perahia, D.Simões, R. P. [UNESP]Magro, A. J. [UNESP]Scott, A. L.2023-07-29T12:54:21Z2023-07-29T12:54:21Z2023-06-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.jmgm.2023.108443Journal of Molecular Graphics and Modelling, v. 121.1873-42431093-3263http://hdl.handle.net/11449/24692710.1016/j.jmgm.2023.1084432-s2.0-85149283407Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal of Molecular Graphics and Modellinginfo:eu-repo/semantics/openAccess2023-07-29T12:54:21Zoai:repositorio.unesp.br:11449/246927Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:46:46.027368Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
title |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
spellingShingle |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods Gasparini, P. Main protease Molecular dynamics Mutation Normal modes Quantum mechanics Residue F140 SARS-CoV-2 Structural dynamics |
title_short |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
title_full |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
title_fullStr |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
title_full_unstemmed |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
title_sort |
Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods |
author |
Gasparini, P. |
author_facet |
Gasparini, P. Philot, E. A. Pantaleão, S. Q. Torres-Bonfim, N. E.S.M. Kliousoff, A. Quiroz, R. C.N. Perahia, D. Simões, R. P. [UNESP] Magro, A. J. [UNESP] Scott, A. L. |
author_role |
author |
author2 |
Philot, E. A. Pantaleão, S. Q. Torres-Bonfim, N. E.S.M. Kliousoff, A. Quiroz, R. C.N. Perahia, D. Simões, R. P. [UNESP] Magro, A. J. [UNESP] Scott, A. L. |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Federal do ABC (UFABC) Universidade Estadual Paulista (UNESP) LBPA |
dc.contributor.author.fl_str_mv |
Gasparini, P. Philot, E. A. Pantaleão, S. Q. Torres-Bonfim, N. E.S.M. Kliousoff, A. Quiroz, R. C.N. Perahia, D. Simões, R. P. [UNESP] Magro, A. J. [UNESP] Scott, A. L. |
dc.subject.por.fl_str_mv |
Main protease Molecular dynamics Mutation Normal modes Quantum mechanics Residue F140 SARS-CoV-2 Structural dynamics |
topic |
Main protease Molecular dynamics Mutation Normal modes Quantum mechanics Residue F140 SARS-CoV-2 Structural dynamics |
description |
The 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. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29T12:54:21Z 2023-07-29T12:54:21Z 2023-06-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.jmgm.2023.108443 Journal of Molecular Graphics and Modelling, v. 121. 1873-4243 1093-3263 http://hdl.handle.net/11449/246927 10.1016/j.jmgm.2023.108443 2-s2.0-85149283407 |
url |
http://dx.doi.org/10.1016/j.jmgm.2023.108443 http://hdl.handle.net/11449/246927 |
identifier_str_mv |
Journal of Molecular Graphics and Modelling, v. 121. 1873-4243 1093-3263 10.1016/j.jmgm.2023.108443 2-s2.0-85149283407 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Journal of Molecular Graphics and Modelling |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1808129356273287168 |