The distance between the carbonyl carbon of the inhibitors and the cysteine S atom is around 3 Å for all the equilibrated inhibitor-bound M pro complexes (Figure ). For both 11a and GC373 M pro complexes, the thiol side chain of Cys145 forms a direct hydrogen bonding interaction with the N " of His41 (Fig. ; Top). On the other hand, for MI-30 and PF-231 M pro complexes, we observe a hydrogen bond between Cys145 thiol side chain and a nearby water molecule (Fig. ; Bottom). In fact, studies have shown than both His41 and conserved catalytic water molecules in the protein active site play an active role in the reaction mechanism of the M pro . As a minor caveat, only the protonation states of His41 was explored in our model complexes due to its significant role in the binding mechanism. Binding free energy simulations that can model the dynamic variation in residue protonation and tautomeric states will be useful to explore the influence of other titratable residues-although not the focus of this study.