title: Influence of backbone conformations of human carbonic anhydrase II on carbon dioxide hydration: hydration pathways and binding of bicarbonate.
abstract: In this study, the hydration of carbon dioxide and the formation of bicarbonate in human carbonic anhydrase II have been examined. From semiempirical QM/MM molecular dynamics studies, dominant conformations of the protein backbone, possibly contributing to the catalytic activity, have been isolated and further examined by means of density functional QM/MM methods. In agreement with experimental observations, a binding site for cyanate, which acts as an inhibitor, has been located, whereas for carbon dioxide, depending on the conformation of the protein environment, either a different binding site or no binding site has been found. In the latter case, carbon dioxide diffuses barrierless to the zinc-bound oxygen, and then a weakly bound bicarbonate complex is formed. The formed complex is characterized by a long C-O bond to the zinc-bound hydroxide. The nature of the calculated stationary points was verified by determination of vibrational frequencies. Finally, the dissociation of the formed bicarbonate from zinc has been considered. Therefore, a water molecule was included in the QM zone of the QM/MM hybrid potential, and minimization yielded a pentacoordinated intermediate. From a potential energy scan, an activation energy of 6.2 kcal/mol for dissociation of bicarbonate from Zn has been found.
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Loferer
authors.forename: Christofer S
authors.initials: CS
authors.lastname: Tautermann
authors.forename: Hannes H
authors.initials: HH
authors.lastname: Loeffler
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D001639:Bicarbonates / Q000737:chemistry* / Q000378:metabolism; D002245:Carbon Dioxide / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D008956:Models, Chemical; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000737:chemistry
chemical_list: D001639:Bicarbonates; D014867:Water; D002245:Carbon Dioxide; D024402:Carbonic Anhydrase II; D015032:Zinc