AN ABINITIO STUDY OF TRANSITION STRUCTURES AND ASSOCIATED PRODUCTS IN [ZNOHCO2]+, [ZNHCO3H2O]+, AND [ZN(NH3)3HCO3]+ HYPERSURFACES - ON THE ROLE OF ZINC IN THE CATALYTIC MECHANISM OF CARBONIC-ANHYDRASE

The zinc hydroxide mechanism has been studied on a series of zinc complexes with and without ammonia coordination shell in the RHF SCF framework using extended basis sets, (14s,9p,5d) for Zn and (9s,5p) for O, C, and N. Saddle points, minima and related force constants, and geometries are reported for the energy hypersurfaces of [ZnOHCO2]+ and [ZnHCO3H2O]+. In the [ZnOHCO2]+ hypersurface, transition structures corresponding to interconversion and productive binding of bicarbonate (monodentate complex with zinc) have been characterized. On the [ZnHCO3H2O]+ hypersurface active and passive (displacement) solvation effects on HCO3- binding to zinc have been studied. The MP2 reactive energy profile basically conserves the inverted shape found at the SCF level. For the ammonia liganded complexes calculations, the following points have been examined: (i) zinc hydroxide nucleophilicity and basicity compared to the bare zinc results; (ii) effects on bicarbonate/water exchange energy balance; (iii) characterization of the monodentate HCO3- binding structure on the energy hypcrsurface spanned by the full set of geometrical variables, followed by an exploration of the resulting transition vector; and (iv) pyramidal and tetrahedral coordination models of zinc cation. The saddle point character of bicarbonate monodentate binding to zinc is conserved; if HCO3- is allowed to move along one of its transition vector directions (which describes an intramolecular rotation-like motion of the HCO3- moiety) a channel toward the interconversion process is opened. Along this reactive pathway, the coordination state of zinc oscillates between tetra- and pentacoordination. The coordination shell accentuates the inverted nature for the energy profile leading to interconversion. This profile can be naturally correlated to the molecular events of the zinc hydroxide mechanism. Bare zinc roles in the carbon dioxide hydroxylation can be summarized as the following: (i) inhibition of simple hydroxide nucleophilicity strength; (ii) carbon dioxide carbonyl activation; (iii) well-defined interconversion pathway at the bottom of an inverted energy profile with low activation barrier; and (iv) formation of a monodentate bicarbonate complex having a saddle point nature: a bicarbonate productive binding. Molecular docking of the ab initio stationary geometries onto the active site of the X-ray structures of various CAs have been performed by using frodo software. A detailed molecular mechanism can be proposed where Thr-199 plays a central role. © 1990, American Chemical Society. All rights reserved.