Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach
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Title
Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM ApproachAuthor (s)
Date
2021-12-28Publisher
MDPIISSN
1422-0067Bibliographic citation
Silva, J.R.A.; Urban, J.; Araújo, E.; Lameira, J.; Moliner, V.; Alves, C.N. Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach. Int. J. Mol. Sci. 2022, 23, 300. https://doi.org/ 10.3390/ijms23010300Type
info:eu-repo/semantics/articleVersion
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Abstract
The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery
projects. Nonstructural proteins ... [+]
The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery
projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication
since it protects the virus from host innate immune restriction. In particular, nonstructural protein 16
(nsp16) in complex with nsp10 is a Cap-0 binding enzyme. The heterodimer formed by nsp16-nsp10
methylates the 50
-end of virally encoded mRNAs to mimic cellular mRNAs and thus it is one of the
enzymes that is a potential target for antiviral therapy. In this study, we have evaluated the mechanism of the 20
-O methylation of the viral mRNA cap using hybrid quantum mechanics/molecular
mechanics (QM/MM) approach. It was found that the calculated free energy barriers obtained at
M062X/6-31+G(d,p) is in agreement with experimental observations. Overall, we provide a detailed
molecular analysis of the catalytic mechanism involving the 20
-O methylation of the viral mRNA cap
and, as expected, the results demonstrate that the TS stabilization is critical for the catalysis. [-]
Is part of
International Journal of Molecular Sciences, Vol. 23 (2022)Funder Name
National Council for Scientific and Technological Development
Project code
CNPq grant 402572/2018-1
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