Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design

The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. same PT likely also required for the covalent binding of some inhibitors. Here we use multiscale computational approach investigate thermodynamics apo enzyme and complex with two potent inhibitors, N3 ?-ketoamide 13b. We show that inhibitors free energy cost reach charge-separated state active-site dyad lower, inducing most significant reduction. few key sites (including specific water molecules) significantly enhance or reduce thermodynamic feasibility reaction, selective desolvation active site playing crucial role. presented cost-effective procedure identify regions control activation thus useful guide design