Ab initio calculations of proton dissociation energies of zinc ligands: Hypothesis of imidazolate as zinc ligand in proteins

Despite intensive studies of zinc's role in proteins and recent growing appreciation of zinc in modem biology, the knowledge of the protonation state of common zinc ligands in proteins remains controversial. Water, the side chains of Glu, Asp, and Cys residues, and even the peptide nitrogen atom are treated as a deprotonated, negatively charged ligand in the zinc complexes in proteins, whereas the side chain of His residue is treated as a neutral ligand in the zinc complexes regardless of the common knowledge that the imidazole nitrogen proton is more acidic than the peptide nitrogen proton. In an attempt to resolve this controversy, we performed large basis set DFT calculations of proton dissociation energies of common zinc ligands in the presence and absence of Zn2+. Herein, we report the results of our calculations revealing that the proton dissociation energies of H2O, MeOH, MeSH, imidazole, and N-methylacetamide are dramatically reduced when they coordinate to Zn2+ and that the proton dissociation energy of the zinc-bound imidazole is 4 kcal/mol lower than that of the zinc-bound N-methylacetamide that is known to be deprotonated according to the X-ray and NMR studies. The result thus suggests further investigations of the possibility of imidazolate as a zinc ligand in proteins.