Computational calculations of pKa values of imidazole in Cu(ii) complexes of biological relevance

The imidazole ring is part of the lateral chain of histidine. One of the main features of this amino acid is the ability to coordinate copper, especially Cu2+, because of the intermediate base nature of its imidazole ring, which has a great biological relevance. Proteins such as cytochrome c oxidase, a crucial enzyme in the respiratory chain, and β-amyloid peptide, implicated in the pathology of Alzheimer's disease, are examples of proteins containing histidines in their coordination sphere. Several studies indicate that the presence of this metal ion produces a decrease in the pKa of the imidazole ring of histidine. However, there are no reports of systematic studies of pKa variation in these types of metal cation complexes. In this work we use density functional theory to study the dependence of imidazole pKa with the number of imidazole rings in Cu2+ coordination environments. The pKa of isolated imidazole (ImH), and the pKa of imidazole in Cu2+(ImH)m(H2O)4−m (m = 1–3) complexes have been studied using two different functionals, B3LYP and MPWB1K, which have different percentage of exact exchange, and the highly-correlated CCSD(T) method. Results show that imidazole pKa decreases between 2 and 7 units depending on the method employed and the number of imidazole rings coordinating the metal cation. Taking into account that the pKa of imidazole is 14, this decrease could be relevant in biological processes.