One might be tempted to claim that the relatively small size of HCO3 -and CO2 molecules allow for simple passage between zones. To address this point, we conducted another 100 ns MD simulation with HCO3 -in its original crystallographic hydrophilic zone. Interestingly, we did not observe any transition between the zones. However, after 40 ns of simulation, the HCO3 -escape from the hydrophilic cavity, demonstrating its dynamic behavior. (cf. Figure ). This result leads to the conclusion that the interaction between the CO2 and its surrounding enzyme environment regulates this zone transformation event. This occurs because the residue at the hydrophilic region repels the hydrophobic CO2 and makes it unstable, resulting its transition to the hydrophobic zone. Conversely, when we perform simulations with the CO2 initially placed in the hydrophobic region, we do not observe any zone transformation events; instead, the CO2 remains primarily in the hydrophobic zone for most of the simulation time, displaying its strong binding affinity to the surrounding residues (cf. Figure ). As shown in Figures , a synchronized choreography of the residues Phe483, Tyr474, Tyr503, and Phe504 is observed to facilitate the CO2 transition. The diffusion of CO2 starts with a slight tilting of the phenyl ring of the Tyr503 residue, followed by an opening of the doorway formed by the aromatic dyad of Phe483 and Phe504. This is further facilitated by a pull-back movement of Tyr474, assisting the migration of CO2 to the hydrophobic half the CA (cf. Figure ). Interestingly, Phe504 shows a farfetched movement that is well synchronized with the movement of the CO2 molecule. As seen in Figure , it regulates the CO2 diffusion by opening and closing the doorway through a 90º plane switch. This highlights its strategic importance in allowing CO2 to pass from one zone to another, while preventing HCO3 -from doing so. Therefore, we termed Phe504 as a 'gatekeeper' residue. Nevertheless, once CO2 arrives in the hydrophobic zone, all residues restore their initial position to transfer the next round of CO2 (cf. Figure ). While we recognize that this is one of the most prominent entry pathways for CO2, we also do not deny the possibility of multiple entry pathways being present.