Copper-peptide complex structure and reactivity when found in conserved His-X_aa-His sequences

Oxygen-activating copper proteins may possess His-X_aa-His chelating sequences at their active sites and additionally exhibit imidiazole group δN vs εN tautomeric preferences. As shown here, such variations strongly affect copper ions coordination geometry, redox behavior, and oxidative reactivity. Copper(I) complexes bound to either δ-HGH or ε-HGH tripeptides were synthesized and characterized. Structural investigations using X-ray absorption spectroscopy, density functional theory calculations, and solution conductivity measurements reveal that δ-HGH forms the Cu^I dimer complex [{Cu^I(δ-HGH)}₂]²⁺ (1) while ε-HGH binds Cu^I to give the monomeric complex [Cu^I(ε-HGH)]⁺ (2). Only 2 exhibits any reactivity, forming a strong CO adduct, [Cu^I(ε-HGH)(CO)]⁺, with properties closely matching those of the copper monooxygenase PHM. Also, 2 is reactive toward O₂ or H₂O₂, giving a new type of O₂-adduct or Cu^II-OOH complex, respectively.