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Article

Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach

1
Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belem 66075-110, Brazil
2
Institute of Biological Sciences, Federal University of Pará, Belem 66075-110, Brazil
3
BioComp Group, Institute of Advanced Materials (INAM), Universitat Jaume I, 12071 Castellon, Spain
*
Authors to whom correspondence should be addressed.
Academic Editors: Francesco Caruso and Miriam Rossi
Int. J. Mol. Sci. 2022, 23(1), 300; https://doi.org/10.3390/ijms23010300
Received: 1 November 2021 / Revised: 10 December 2021 / Accepted: 23 December 2021 / Published: 28 December 2021
(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)
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 5′-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 2′-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 2′-O methylation of the viral mRNA cap and, as expected, the results demonstrate that the TS stabilization is critical for the catalysis. View Full-Text
Keywords: SARS-CoV-2; nsp16-nsp10; 2′-O methylation; catalytic mechanism; QM/MM; TS stabilization; free energy SARS-CoV-2; nsp16-nsp10; 2′-O methylation; catalytic mechanism; QM/MM; TS stabilization; free energy
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MDPI and ACS Style

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/ijms23010300

AMA Style

Silva JRA, Urban J, Araújo E, Lameira J, Moliner V, Alves CN. Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach. International Journal of Molecular Sciences. 2022; 23(1):300. https://doi.org/10.3390/ijms23010300

Chicago/Turabian Style

Silva, José Rogério A., Jaime Urban, Edson Araújo, Jerônimo Lameira, Vicent Moliner, and Cláudio Nahum Alves. 2022. "Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach" International Journal of Molecular Sciences 23, no. 1: 300. https://doi.org/10.3390/ijms23010300

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