The coordination chemistry of the catalytic zinc ion in alcohol dehydrogenase studied by ab initio quantum chemical calculations

The coordination chemistry of the zinc ion in the active site of alcohol 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 MP 2 level. The active site was modeled by Zn(HS)₂XL(H₂O)_0–2, where X denotes ammonia or imidazole and L denotes water, methanol, ethanol, or the corresponding aldehydes or anions. It is shown that with uncharged L-ligands the four-coordinate complexes are about 20, 17, and 40kJ/mol more stable than are the corresponding three-, five-, and six-coordinate complexes, respectively. If the L-ligand is negatively charged, only the four-coordinate complexes are stable. These results suggest 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 intermittent formation of a five-coordinate complex. The results lend no support to mechanistic proposals attributing an important catalytic role to a negatively charged five-coordinate hydroxide or alkoxide ligand. © 1994 John Wiley & Sons, Inc.