title: Molecular dynamics study of human carbonic anhydrase II in complex with Zn(2+) and acetazolamide on the basis of all-atom force field simulations.
abstract: 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.
authors.affiliation: Department of Physics, University of Texas at San Antonio, San Antonio, TX 78249, USA.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Wambo
authors.affiliation: Department of Physics, University of Texas at San Antonio, San Antonio, TX 78249, USA. Electronic address: liao.chen@utsa.edu.
authors.forename: Liao Y
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Texas at San Antonio, San Antonio, TX 78249, USA.
authors.forename: Stanton F
authors.initials: SF
authors.lastname: McHardy
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Tsin
mesh_terms: D000086:Acetazolamide / Q000737:chemistry / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D024402:Carbonic Anhydrase II; D015032:Zinc; D000086:Acetazolamide
keywords: Free energy of binding; Human carbonic anhydrase; Metalloenzyme; Protein-ligand interaction; Protein-metal interaction