Impact of Early Pandemic Stage Mutations on Molecular Dynamics of SARS-CoV-2 Mpro

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A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (Mpro), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of Mpro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant Mpro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, Rg, averaged betweenness centrality, and geometry calculations. The results showed that SARS-CoV-2 Mpro essentially behaves in a similar manner to its SAR-CoV homolog. However, we report the following new findings from the variants: (1) Residues GLY15, VAL157, and PRO184 have mutated more than once in SARS CoV-2; (2) the D48E variant has lead to a novel “TSEEMLN”” loop at the binding pocket; (3) inactive apo Mpro does not show signs of dissociation in 100 ns MD; (4) a non-canonical pose for PHE140 widens the substrate binding surface; (5) dual allosteric pockets coinciding with various stabilizing and functional components of the substrate binding pocket were found to display correlated compaction dynamics; (6) high betweenness centrality values for residues 17 and 128 in all Mpro samples suggest their high importance in dimer stability—one such consequence has been observed for the M17I mutation whereby one of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between the rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modeling, dynamic residue network (DRN), relevant conformation retrieval from 1-D kernel density estimates from reaction coordinates to other existing approaches of structural analysis, and data visualization within the coronaviral Mpro is also novel and is applicable to other coronaviral proteins.


This article was originally published in Journal of Chemical Information and Modeling in 2020. https://doi.org/10.1021/acs.jcim.0c00634

This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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American Chemical Society