Molecular dynamics study of human carbonic anhydrase II in complex with Zn(2+) and acetazolamide on the basis of...

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 Zn(2+) (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 Zn(2+) 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 Zn(2+), the characteristics of hCAII-Zn(2+) complexation, and the absolute free energy of binding acetazolamide to the hCAII-Zn(2+) 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.