Key role of histidine residues orientation in affinity binding of model pentapeptides with Ni2+ ions: A theoretical supported experimental study

Abstract Understanding the metal ion-protein interactions is crucial in transport, accumulation, and excretion of metals. Furthermore, it seems to be highly important to investigate the role of such complexes in many diseases, such as cancer and neurodegenerative disorders. Unexpectedly, such studies in the systems comprising peptides and Ni2+ ions are still scarce and should be given more importance – particularly considering the toxicity and carcinogenicity of nickel compounds on the living organisms. We report herein the results of a study on the interactions of Ni2+ ions and four pentapeptide analogs: EYHHQ (p1), EHYHQ (p2), HEYHQ (p3), and HEYQH (p4). Potentiometric titration was used to study acid-base properties as well as binding properties of the investigated peptides. Furthermore, stoichiometry of the peptide complexes with Ni2+ ions was evaluated by steady-state fluorescence spectroscopy and potentiometric titration method. Additionally, based on the density functional theory (DFT) calculations, we propose the most likely structures of the complexes of the peptides p1-p4 with Ni2+ ions. It was found that all the peptides form 1:1 and 1:2 thermodynamically stable complexes with Ni2+ cation. In particular, we observed that the interaction between the metal ion and histidine-containing peptide sequences does not depend only on histidines splicing, but also on their orientation in respect to other amino acids in the sequence. Also, the closer proximity of His residue in these short peptides does not increase complex stability, due to stacking interaction between the neighboring imidazole rings.