Solvent effects on the physicochemical properties of the cross-linked histidine-tyrosine ligand of cytochrome c oxidase.

Density functional theory was used to explore the effects of aqueous solvation on the structure, vibrational frequencies, and the electronic absorption spectrum of 2-(4-methylimidazol-1-yl)-phenol (Me-ImPhOH), a chemical analogue of the cross-linked histidine-tyrosine Cu(B) ligand of cytochrome c oxidase. In addition, the phenolic-OH pK(a), the anodic redox potential for the biring radical/anion couple, and the phenolic-OH bond dissociation energy were calculated relative to phenol using a series of isodesmic reactions. In the gas phase, the imidazole moiety stabilizes the biring anion for all the models and greatly decreases the phenolic-OH pK(a) relative to phenol. Moreover, the conductor-like polarizable continuum model (C-PCM)-water-solvated reactions predict Delta pK(a) values that are five times smaller than the gas-phase reactions, in agreement with the proposed role of the cross-linked histidine-tyrosine as a proton donor in the enzyme. For the neutral biring radical solvation models, the imidazole moiety induces a high degree of asymmetry into the phenol ring when compared to unmodified phenoxyl radical. The biring radical pi-bonds of the imidazole ring are more localized when compared to unmodified 1-methylimidazole and Me-ImPhOH solvation models, suggesting reduced aromaticity for all biring radical solvation models. The C-PCM-water-solvated reactions predict relative biring radical reduction potentials that are an order of magnitude smaller than the gas-phase reactions. The biring O-H bond is weakened relative to phenol by less than 4 kcal/mol for all the reactions studied, suggesting that the imidazole moiety does not facilitate H-atom abstraction in the enzyme. Together, these results demonstrate the sensitive nature of the proton and electron donating ability of the histidine-tyrosine cross-linked ligand in cytochrome c oxidase and suggest that for quantitative predictions of reaction energies and thermodynamic properties, models of this ligand should take care to account for changes in environment and, more specifically, hydrogen bonding interactions.