tetano
Editor, Senior Moderator
J Chem Inf Model
. 2020 Aug 27.
doi: 10.1021/acs.jcim.0c00634. Online ahead of print.
Impact of early pandemic stage mutations on molecular dynamics of SARS-CoV-2 M [SUP]pro[/SUP]
Olivier Sheik Amamuddy, Gennady M Verkhivker, ?zlem Tastan Bishop
Abstract
The new coronavirus (SARS-CoV-2) is a global threat to the world health and economy. Its dimeric main protease (M[SUP]pro[/SUP]), 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 M[SUP]pro[/SUP] behaviour can accelerate the discovery of effective therapies to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 mutant M[SUP]pro[/SUP] dimers obtained from filtered sequences from the GISAID database were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. The results showed that SARS-CoV-2 M[SUP]pro[/SUP] 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 substrate binding surface; (5) dual allosteric pockets coinciding with various stabilising 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 M[SUP]pro[/SUP] samples suggest their high importance in dimer stability - one such consequence has been observed for the M17I mutation whereby on of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modelling, 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 visualisation within the coronaviral M[SUP]pro[/SUP] is also novel and is applicable to other coronaviral proteins
. 2020 Aug 27.
doi: 10.1021/acs.jcim.0c00634. Online ahead of print.
Impact of early pandemic stage mutations on molecular dynamics of SARS-CoV-2 M [SUP]pro[/SUP]
Olivier Sheik Amamuddy, Gennady M Verkhivker, ?zlem Tastan Bishop
- PMID: 32853525
- DOI: 10.1021/acs.jcim.0c00634
Abstract
The new coronavirus (SARS-CoV-2) is a global threat to the world health and economy. Its dimeric main protease (M[SUP]pro[/SUP]), 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 M[SUP]pro[/SUP] behaviour can accelerate the discovery of effective therapies to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 mutant M[SUP]pro[/SUP] dimers obtained from filtered sequences from the GISAID database were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. The results showed that SARS-CoV-2 M[SUP]pro[/SUP] 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 substrate binding surface; (5) dual allosteric pockets coinciding with various stabilising 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 M[SUP]pro[/SUP] samples suggest their high importance in dimer stability - one such consequence has been observed for the M17I mutation whereby on of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modelling, 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 visualisation within the coronaviral M[SUP]pro[/SUP] is also novel and is applicable to other coronaviral proteins