Molecular dynamics study of human carbonic anhydrase II in complex with Zn2+ and acetazolamide on the basis of all-atom force field simulations

- All-atom molecular dynamics of the most efficient metalloenzyme in agreement with experimental data
- A simple representation of the divalent cation Zn2+ shown to be accurate enough for its hydration, its complexation with hCAII, and the binding affinity of an inhibitor it co-effects.

Human carbonic anhydrase II (hCAII) represents an ultimate example of the perfectly efficient metalloenzymes, which is capable of catalyzing the hydration of carbon dioxide with a rate approaching the diffusion controlled limit. Extensive experimental studies of this physiologically important metalloprotein have been done to elucidate the fundamentals of its enzymatic actions: what residues anchor the Zn2+ (or another divalent cation) at the bottom of the binding pocket; how the relevant residues work concertedly with the divalent cation in the reversible conversions between CO2 and HCO3-; what are the protonation states of the relevant residues and acetazolamide, an inhibitor complexed with hCAII, etc. In this article, we present a detailed computational study on the basis of the all-atom CHARMM force field where Zn2+ is represented with a simple model of divalent cation using the transferrable parameters available from the current literature. We compute the hydration free energy of Zn2+, the characteristics of hCAII-Zn2+ complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn2+ complex. In each of these three problems, our computed results agree with the experimental data within the known margin of error without making any case-by-case adjustments to the parameters. The quantitatively accurate insights we gain in this all-atom molecular dynamics study should be helpful in the search and design of more specific inhibitors of this and other carbonic anhydrases.