As shown in Scheme 1, the hydration of CO2 by CA requires a proton acceptor and a water molecule to complete its catalytic cycle. Similarly, it is also supported by our QM-only DFT studies (cf. S.2. and Figure for thorough discussion). As such, there could be two possible catalytic pathways: stepwise and concerted. In the stepwise pathway, the OH -is first produced and then undergoes a nucleophilic attack on CO2 (cf. Figure ), whereas in the concerted pathway, the formation of OH -and its nucleophilic attack on CO2 occur simultaneously (cf. Figure ). In both cases, OH -is produced by deprotonating a water molecule, with a proton acceptor residue playing a crucial role. So far, it is widely accepted that in CA, a His residue acts as the proton acceptor by shuttling the proton to the bulk water. Although some mutational studies suggest that Lys and Glu can also serve as proton acceptor residues, they are much less efficient than His. In a more general context, there may be other residues such as Thr, Ser, Arg, etc. that could potentially assist in transferring protons from one residue to another. As such, we conducted an analysis to identify potential proton-accepting or proton-shuttling residues within a proximity of 5 Å around the CO2 throughout the MD trajectory (cf. Figure ) and calculated the distribution percentage of these residue in the vicinity of 5 Å of CO2 in both the hydrophilic zone (up to ~28 ns) and the hydrophobic zone (after ~28 ns to 100 ns) as shown in Figure . In addition, we provide the radial distribution function (RDF) plot for CO2 and all these key amino acid residues in the SI (cf. Figure ).