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

Abstract

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 pK_a of the imidazole ring of histidine. However, there are no reports of systematic studies of pK_a variation in these types of metal cation complexes. In this work we use density functional theory to study the dependence of imidazole pK_a with the number of imidazole rings in Cu²⁺ coordination environments. The pK_a of isolated imidazole (ImH), and the pK_a 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 pK_a 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 pK_a of imidazole is 14, this decrease could be relevant in biological processes.