Kinetics of CO2 diffusion in human carbonic anhydrase: a study using molecular dynamics simulations and the Markov-state model

Abstract

Molecular dynamics (MD) simulations, in combination with the Markov-state model (MSM), were applied to probe CO₂ diffusion from an aqueous solution into the active site of human carbonic anhydrase II (hCA-II), an enzyme useful for enhanced CO₂ capture and utilization. The diffusion process in the hydrophobic pocket of hCA-II was illustrated in terms of a two-dimensional free-energy landscape. We found that CO₂ diffusion in hCA-II is a rate-limiting step in the CO₂ diffusion-binding-reaction process. The equilibrium distribution of CO₂ shows its preferential accumulation within a hydrophobic domain in the protein core region. An analysis of the committors and reactive fluxes indicates that the main pathway for CO₂ diffusion into the active site of hCA-II is through a binding pocket where residue Gln¹³⁶ contributes to the maximal flux. The simulation results offer a new perspective on the CO₂ hydration kinetics and useful insights toward the development of novel biochemical processes for more efficient CO₂ sequestration and utilization.