SARS-CoV-2's main protease (Mpro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, Mpro 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 Mpro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 μs 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 Mpro 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 Mpro.Communicated by Ramaswamy H. Sarma.
Keywords: COVID-19; Molecular dynamics simulation; Mpro; main protease.