The main-protease (M pro ) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (M CoV2 pro ) with 12 mutations compared to SARS-CoV (M CoV1 pro ). Recent studies point out that these subtle differences lead to mobility variances at the active site loops with functional implications. We use metadynamics simulations and a sort of computational analysis to probe the dynamic, pharmacophoric and catalytic environment differences between the monomers of both enzymes. So, we verify how much intrinsic distinctions are preserved in the functional dimer of M CoV2 pro , as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the M CoV2 pro monomer compared to M CoV1 pro . A higher hydration propensity for the M CoV2 pro S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for M CoV2 pro are less catalytically active in the monomer. However, the statistics for contacts involving the N-finger suggest higher maintenance of this activity at the dimer. Docking analyses suggest that the ability to vary the active site width can be important to improve the access of the ligand to the active site in different ways. So, we carry out a multiconformational virtual screening with different ligand bases. The results point to the importance of taking into account the protein conformational multiplicity for new promissors anti M CoV2 pro ligands. We hope these results will be useful in prospecting, repurposing and/or designing new anti SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma

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