Could the tyrosine-histidine ligand to CuB in cytochrome c oxidase be coordinatively labile? Implications from a quantum chemical model study of histidine substitutional lability and the effects of the covalent tyrosine-histidine cross-link

Abstract

Density functional theory calculations have been used to evaluate the effects of inter-ring interactions within a covalently linked histidine-tyrosine cofactor such as that which is a ligand to the Cu(B) centre in cytochrome c oxidases and to investigate the energetics of histidine substitution at the Cu(B) centre. Small, but significant, perturbations of the redox potentials and/or p K(a) values of the histidine imidazole, the tyrosine phenol and the copper ion are found. The Cu(B)-N(cofactor) bond is estimated to be weaker than the Cu(B)-N(histidine coligand) bonds in the Cu(B)(I) state and in the Cu(B) (II) state when the cofactor is oxidized, by approximately 13 kJ/mol and approximately 23 kJ/mol, respectively. The calculations reveal that displacement of a histidine ligand from the Cu(B) centre, as is suggested in proposals of "histidine cycle" mechanisms for proton pumping in cytochrome c oxidases, is only energetically feasible if accompanied by protonation of the histidine imidazole and coupled to an endothermic process. It is proposed that the histidine-tyrosine cofactor ought to be considered as the substitutionally labile ligand to Cu(B) as the covalent crosslink would ensure displacement of the cofactor from Cu(B)-driven helix deformation. It is estimated that this process could store up to approximately 70 kJ/mol, which, based upon thermodynamic considerations, is sufficient for the pumping of two protons in the later steps (reductive phase) of the catalytic cycle. Ramifications of this proposition for the mechanism of proton pumping in cytochrome c oxidases are discussed.

Effects of Imidazole-Type Ligands in CuI/TEMPO-Mediated Aerobic Alcohol Oxidation

“…In the corresponding UV–vis spectra, such slight changes in the coordination sphere of (bpy)­Cu II (NMI) are reflected by a small change in the d–d band when more than 1.0 equiv of NMI is added (Figure B). This indicates weak coordination of an additional NMI molecule − and is in accordance with the fact that IM-type ligands are known as labile ligands in biological systems. − The labile coordination of NMI to the Cu I center may be of vital importance for electron transfer from Cu I to O 2 because one coordinating NMI ligand is supposed to be temporarily displaced from the Cu center to enable O 2 adsorption and subsequent superoxide formation. From in situ IR measurements at −40 °C, we obtained experimental support that this may indeed happen (Figure S7).…”

Model studies of the CuBsite of cytochrome c oxidase utilizing a Zn(ii) complex containing an imidazole–phenol cross-linked ligand

“…Furthermore, their computational data are consistent with our previous experimental observation 10 that formation of a phenoxyl radical results in a significant decrease in the basicity of the coordinating imidazole imino nitrogen. 25 To date, no experimental or theoretical studies have focused on the influence of phenolate formation on the coordination chemistry of an imidazole-phenol ligand bound to a divalent metal ion via the imidazole. The present study was directed towards understanding the role of a metal ion in perturbing the physicochemical properties (pK a , oxidation potential) of the cross-linked phenol, and its corresponding aqueous coordination chemistry as a function of pH, in complexes that maintain the dihedral angle observed in the enzyme.…”

Evolutionary Migration of a Post-Translationally Modified Active-Site Residue in the Proton-Pumping Heme-Copper Oxygen Reductases

“…Conversely, the redox state and protonation state of the tyrosine influence the electron donating capacity of the imidazole as a metal ligand, thus controlling the preferred ligand geometry about Cu B (35). It has also been suggested that, due to the presence of the crosslinked tyrosine, the histidine ligand to Cu B might be labile and move away from the metal during turnover, playing a key role in the proton pump mechanism (40). These studies, in conjunction with the presence of the crosslinked cofactor in all oxygen reductase families, suggests that the cofactor may be a required component for proton pumping.…”

“…Recent studies with model compounds (35)(36)(37)(38)(39) as well as computational studies (26,40) have suggested a possible functional significance for the crosslink. The crosslinked histidine withdraws electrons from the tyrosine, resulting in a lower pKa and a higher midpoint potential of the tyrosine (41).…”