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The main protease, M pro /3CL pro , plays an essential role in processing polyproteins translated from viral RNA to produce functional viral proteins and therefore serve as an attractive target for discovering COVID-19 therapeutics. The availability of both monomer and dimer crystal bound with a common ligand, ‘13b’ (α-ketoamide inhibitor), opened up opportunities to understand the M pro  mechanism of action. A comparative analysis of both forms of M pro  was carried out to elucidate the binding site architectural differences in the presence and absence of ‘13b’. Molecular dynamics simulations suggest that the presence of ‘13b’ enhances the stability of M pro  than the unbound APO form. The N- and C- terminals of both the protomers stabilize each other, and making it's interface essential for the active form of M pro . In comparison to monomer, the relatively high affinity of ‘13b’ is gained in dimer pocket due to the high stability of the pocket by the interaction of S1 residue of chain B with residues F140, E166 and H172 of chain A, which is absent in monomer. The comprehensive essential dynamics, protein structure network analysis and thermodynamic profiling highlight the  hot-spots , pivotal in molecular recognition process at protein-ligand and protein-protein interaction levels, cross-validated through computational alanine scanning study. A comparative description of ‘13b’ binding mechanism in both forms illustrates valuable insights into the inhibition mechanism and the selection of critical residues suitable for the structure-based approaches for the identification of more potent M pro  inhibitors. Communicated by Ramaswamy H. Sarma

Binding mode characterization of 13b in the monomeric and dimeric states of SARS-CoV-2 main protease using molecular dynamics simulations