Exploring the possibility of high-valent copper in models of copper proteins with a three-histidine copper-binding motif

An important function of many copper-containing proteins is activation of O2 and subsequent substrate oxidation. The Cu (III) oxidation state is generally considered to be less accessible because of the highly positive Cu (III)/Cu (II) redox potentials with typical amino acid ligands. Here, we employ density functional (DFT) calculations to explore to what extent copper (III) may be accessed in a biologically-relevant coordination environment around a mononuclear copper center, by breaking the oxygen-oxygen bond in a copper-(hydro) peroxide complex. In agreement with previous findings by Solomon and co-workers on copper models with related coordination patterns, the formally high-valent copper complex produced by O-O bond cleavage appears to harbor both oxidizing equivalents on the ligands. The potential energy surface for such a reaction reveals that with the three-histidine binding motif at the copper, O-O bond cleavage is not impossible, but rather disfavored thermodynamically.