Interactions within the alcohol dehydrogenase Zn(II)-metalloenzyme active site: Interplay between subvalence, electron correlation/dispersion, and charge transfer/induction effects

Following our preceding works (de Courcy et al. J Chem Theo Comput 2008, 4, 1659; de Courcy, et al. Interdiscip Sci Comput Life Sci 2009, 1, 55), we have studied by quantum chemistry a model of the alcohol dehydrogenase Zn-metalloenzyme (ADH) binding site. Using several interpretative techniques such as the topological analysis of the electron localization function (ELF) and quantum theory of atoms in molecules combined with energy decomposition analysis schemes, we have analyzed the physical origin of the interactions occurring in this site, which is stabilized by an indirect cation-π interaction. While polarization effects are important for the metal, which is able to adapt its outer-shell density (the so-called subvalence domains) to its ligands, they do not play a key role in the overall interaction of the system that is dominated by dispersion. The ELF analysis shows that only minor charge transfer phenomena are observed between the constitutive fragments of the system. From a methodological standpoint, density functional theory functionals appear unable to handle the system whereas dispersion-corrected methods (DFT-D) perform significantly better, giving reasonable answers as compared with post-Hartree-Fock methods. The stabilization energy brought by the presence of Phe93 to the active binding site of ADH is about −3 kcal/mol. The importance of accounting for basis set superposition error is also emphasized. © 2010 Wiley Periodicals, Inc.