SARS-COV-2 Mpro conformational changes induced by covalently bound ligands

SARS-CoV-2's main protease (M-pro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, M-pro is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different M-pro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, similar to 9 mu s per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the M-pro dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring in silico the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 M-pro. Communicated by Ramaswamy H. Sarma

Automated summary

This study systematically simulated the interaction between SARS-CoV-2's M-pro and ligands, revealing that the M-pro dimer exhibited a more stable conformation with increased interaction frequencies with specific residues, which may significantly impact the inhibitory activity of the ligands.