Impact of dimerization and N3 binding on molecular dynamics of SARS-CoV and SARS-CoV-2 main proteases

SARS-CoV-2 main protease is one of the major targets in drug development efforts against Covid-19. Even though several structures were reported to date, its dynamics is not understood well. In particular, impact of dimerization and ligand binding on the dynamics is an important issue to investigate. In this study, we performed molecular dynamics simulations of SARS-CoV and SARS-CoV-2 main proteases to investigate influence of dimerization on the dynamics by modeling monomeric and dimeric apo and holo forms. The dimerization causes an organization of the interdomain dynamics as well as some local structural changes. Moreover, we investigated impact of a peptide mimetic (N3) on the dynamics of SARS-CoV and SARS-CoV-2 Mpro. The ligand binding to the dimeric forms causes some key local changes at the dimer interface and it causes an allosteric interaction between the active sites of two protomers. Our results support the idea that only one protomer is active on SARS-CoV-2 due to this allosteric interaction. Additionally, we analyzed the molecular dynamics trajectories from graph theoretical perspective and found that the most influential residues - as measured by eigenvector centrality - are a group of residues in active site and dimeric interface of the protease. This study may form a bridge between what we know about the dynamics of SARS-CoV and SARS-CoV-2 Mpro. We think that enlightening allosteric communication of the active sites and the role of dimerization in SARS-CoV-2 Mpro can contribute to development of novel drugs against this global health problem as well as other similar proteases. Communicated by Ramaswamy H. Sarma.