THE COORDINATION CHEMISTRY OF THE CATALYTIC ZINC ION IN ALCOHOL-DEHYDROGENASE STUDIES BY AB-INITIO QUANTUM-CHEMICAL CALCULATIONS

The coordination chemistry of the zinc ion in the active site of alcoh ol dehydrogenase has been studied by the ab initio Hartree-Fock method . Geometry optimizations were performed using analytical gradients and basis sets of double-zeta quality. Correlation effects were included at the MP2 level. The active site was modeled by Zn(HS)2XL(H2O)0-2, wh ere X denotes ammonia or imidazole and L denotes water, methanol, etha nol, or the corresponding aldehydes or anions. It is shown that with u ncharged L-ligands the four-coordinate complexes are about 20, 17, and 40kJ/mol more stable than are the corresponding three-, five-, and si x-coordinate complexes, respectively. If the L-ligand is negatively ch arged, only the four-coordinate complexes are stable. These results su ggest that the active-site zinc ion in alcohol dehydrogenase prefers a coordination number of four during the catalytic reaction, especially when the nonprotein ligand is negatively charged. Ligand exchange at the zinc ion is likely to proceed by an associative mechanism with int ermittent formation of a five-coordinate complex. The results lend no support to mechanistic proposals attributing an important catalytic ro le to a negatively charged five-coordinate hydroxide or alkoxide ligan d. (C) 1994 John Wiley & Sons, Inc.