The Critical Role of Histidine in Copper (II) Coordination^†

Histidine (His), as the most chemically active and versatile member among the 20 natural amino acids, plays a key role in the coordination of copper (II) (Cu(II)) in biological systems. Cu(II)-His species are ubiquitous in metalloenzymes and proteins associated with various neurodegenerative diseases, where they regulate catalytic activity and mediate intracellular copper transport. While the steric influence of His is known to dictate donor group selection in Cu(II) coordination, the extent of these constraints on peptide complexes remains unclear. In this study, we employed a multi-spectroscopic approach (FTIR, 2D IR, UV-Vis, EPR, and NMR) to systematically investigate pH-dependent Cu(II) coordination in three tripeptides. Our results demonstrate that Cu(II) coordination geometries are cooperatively determined by both the protonation state of the N-terminus and the steric constraints imposed by the His residue.