tetano
Editor, Senior Moderator
J Chem Inf Model
. 2024 Feb 29.
doi: 10.1021/acs.jcim.3c01518. Online ahead of print. On Inactivation of the Coronavirus Main Protease
Hong Ha Nguyen[SUP] 1 [/SUP], Jim Tufts[SUP] 1 [/SUP], David D L Minh[SUP] 1 [/SUP]
Affiliations
A deeper understanding of the inactive conformations of the coronavirus main protease (MPro) could inform the design of allosteric drugs. Based on extensive molecular dynamics simulations, we built a Markov State Model to investigate structural changes that can inactivate the SARS-CoV-2 MPro. In a subset of structures, one subunit of the homodimer assumes an inactive conformation that resembles an inactive crystal structure. However, contradicting the widely held half-of-sites activity hypothesis, the most populated enzyme structures have two active subunits. We then used transition path theory (TPT) and the Jensen-Shannon Divergence (JSD) to pinpoint residues involved in the inactivation process. A π stack between Phe140 and His163 is a key feature that can distinguish active and inactive conformations of MPro. Each subunit has unique inactive conformations stabilized by π stacking interactions involving residues Phe140, Tyr118, His163, and His172, a hydrogen bonding network centered around His163 and His172, and a modified network of interactions in the dimer interface. The importance of these residues in maintaining an active structure explains the sensitivity of enzymatic activity to site-directed mutagenesis.
. 2024 Feb 29.
doi: 10.1021/acs.jcim.3c01518. Online ahead of print. On Inactivation of the Coronavirus Main Protease
Hong Ha Nguyen[SUP] 1 [/SUP], Jim Tufts[SUP] 1 [/SUP], David D L Minh[SUP] 1 [/SUP]
Affiliations
- PMID: 38423522
- DOI: 10.1021/acs.jcim.3c01518
A deeper understanding of the inactive conformations of the coronavirus main protease (MPro) could inform the design of allosteric drugs. Based on extensive molecular dynamics simulations, we built a Markov State Model to investigate structural changes that can inactivate the SARS-CoV-2 MPro. In a subset of structures, one subunit of the homodimer assumes an inactive conformation that resembles an inactive crystal structure. However, contradicting the widely held half-of-sites activity hypothesis, the most populated enzyme structures have two active subunits. We then used transition path theory (TPT) and the Jensen-Shannon Divergence (JSD) to pinpoint residues involved in the inactivation process. A π stack between Phe140 and His163 is a key feature that can distinguish active and inactive conformations of MPro. Each subunit has unique inactive conformations stabilized by π stacking interactions involving residues Phe140, Tyr118, His163, and His172, a hydrogen bonding network centered around His163 and His172, and a modified network of interactions in the dimer interface. The importance of these residues in maintaining an active structure explains the sensitivity of enzymatic activity to site-directed mutagenesis.