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Molecular Dynamics Simulations Suggest Sars-Cov-2 3clpro Mutations in Beta and Omicron Variants do not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins
de Freitas Amorim, V.M.; de Souza, R.F.; Guzzo, C.R.; de Souza, A.S. Molecular Dynamics Simulations Suggest SARS-CoV-2 3clpro Mutations in Beta and Omicron Variants Do Not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins. COVID2023, 3, 622-636.
de Freitas Amorim, V.M.; de Souza, R.F.; Guzzo, C.R.; de Souza, A.S. Molecular Dynamics Simulations Suggest SARS-CoV-2 3clpro Mutations in Beta and Omicron Variants Do Not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins. COVID 2023, 3, 622-636.
de Freitas Amorim, V.M.; de Souza, R.F.; Guzzo, C.R.; de Souza, A.S. Molecular Dynamics Simulations Suggest SARS-CoV-2 3clpro Mutations in Beta and Omicron Variants Do Not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins. COVID2023, 3, 622-636.
de Freitas Amorim, V.M.; de Souza, R.F.; Guzzo, C.R.; de Souza, A.S. Molecular Dynamics Simulations Suggest SARS-CoV-2 3clpro Mutations in Beta and Omicron Variants Do Not Alter Binding Affinities for Cleavage Sites of Non-Structural Proteins. COVID 2023, 3, 622-636.
Abstract
In the course of SARS-CoV-2 infection, the 3CL or nsp5 protease plays a pivotal role as the most important viral protease required for the maturation of viral proteins during host infection. Herein, we simulated for 500 ns 3CLproWT, 3CLproH41A, , 3CLproBeta, and 3CLproOmicron, in complex with the substrates nsp 4|5 and nsp 5|6. Our results show that mutations in the 3CLpro present in the SARS-CoV-2 variant of concerns (VOCs) did not lead to significant conformational changes or changes in substrate binding affinities. However, significantly high cleavage rates for the boundary between nsp4 and nsp5 were obtained for 3CLproBeta and 3CLproOmicron and may play a key role in the viral replication and virus fitness gain. Our molecular dynamics data suggest that the cleavage rate of nsp4|5 may be related to the increased amount of viral load observed for these VOCs, releasing more nsp4 than other non-structural proteins. Based on our hydrogen bonding analyses, we also discovered that Gly143 and Glu166 are key residues in substrate recognition, suggesting that these residues may be incorporated as pharmacophoric centers for Beta and Omicron variants in drug design. Our results suggest that Gly143 and Glu166 are essential residues to interact with Gln6 of the different substrates and, therefore, are potential broad-spectrum pharmacophoric centers of SARS-CoV-2 3CLpro.
Keywords
Molecular Dynamics; SARS-CoV-2 variants of concern; 3CLpro; viral load
Subject
Physical Sciences, Chemical Physics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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