Carbonic anhydrase II simulated with a universal neural network potential

Abstract

The carbonic anhydrase II enzyme (CA II) is one of the most significant enzymes in nature, reversibly converting CO$_2$ to bicarbonate at a remarkable rate. The precise mechanism it uses to achieve this rapid turnover remains unclear due to our inability to directly observe or simulate the full process dynamically. Here, we use a recently developed universal neural network potential (Orb) to simulate the active site of CA II. We reproduce several known features of the reaction mechanism, including the proton relay that conducts protons out of the active site to the His64 residue. Additionally, we observe a new reaction pathway where CO$_2$ reacts with a water molecule in the active site, which donates a proton to the zinc-bound hydroxide. This differs from the established mechanism where CO$_2$ directly reacts with hydroxide. Existing experimental data and independent quantum chemistry calculations are used to support the plausibility of this new mechanism. This demonstrates the potential of Orb to efficiently generate novel insights into important molecular scale processes that can potentially be harnessed to improve CO$_2$ capture technologies and drug design.