Kinetics of CO 2 diffusion in human carbonic anhydrase: a study using molecular dynamics simulations and the Markov-state model.

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.