Revisiting the significance of kinetic inertia in complex formation/decomplexation of metal–ATCUN peptide complexes

Research on copper and nickel complexes formed by an amino terminal Cu(II) and Ni(II) binding (ATCUN) motif has greatly progressed in recent decades. These compounds are of considerable interest in bioinorganic chemistry, both as potential metallodrug candidates and as artificial metalloenzymes. Although the high stability of the Cu(II)- and Ni(II)-ATCUN complexes under physiologically relevant conditions is well established, the kinetic inertia associated with their formation has often been underestimated, particularly in the context of their catalytic applications. Here, we prepared ATCUN peptides (GGHWGKRG-Am; GGH-Pep) and investigated the stability of their Cu(II) and Ni(II)-ATCUN complexes in aqueous solutions under conditions enabling 1 : 1 metal-to-peptide complex formation at micromolar concentrations. Systematic pH titration revealed that the low basicity of the N-terminal amine of the peptide contributes to stabilizing the metal-ATCUN complex in aqueous solution. These findings highlight the need to account for kinetic inertia when evaluating ATCUN-like complexes under catalytically relevant conditions.