The preceding discussion demonstrates the catalytic formation of HCO3 -in the hydrophobic zone. However, in the crystal structure, it is found in the hydrophilic zone, raising questions about its transfer pathway from the hydrophobic zone. Additionally, it is essential to understand why it cannot facilitate the reverse dehydration reaction, a process common in metal-containing CA. One possible explanation is the observed exothermicity of HCO3 -formation (cf. Figure ), which makes it thermodynamically stable and kinetically inert (∆EReverse = ~20.3 kcal/mol). However, other factors related to its dynamics cannot be ignored. As such, we performed additional simulations with HCO3 -, which is initially located in the hydrophobic zone (cf. Figure ). Interestingly, within the initial couple of nanoseconds, HCO3 -leaves the hydrophobic catalytic site (cf. Figure ) and briefly enters the hydrophilic zone, following the pathway typically occupied by bulk water, before exiting that zone as well These movements are illustrated in Figures , with an additional video provided in the SI (cf. Video VS3). Furthermore, the RMSD plot for the enzyme backbone (cf. Figure ) shows stability throughout the simulation, whereas the high fluctuation in the RMSD of HCO3 -(cf.