The evolutionary origin of copper-binding proteins remains a central question in prebiotic chemistry. Modern copper proteins predominantly coordinate copper through histidine and cysteine residues, suggesting that these amino acids were selectively favored during early protein evolution. Here, we propose that ultraviolet (UV) radiation acted as a key selective factor in shaping primordial copper-peptides. Spectroscopic analyses suggest that His2 interacts with Cu(II) through contributions from both its N- and C-terminal donor groups, generating a comparatively stronger binding environment and supporting its plausibility as a primitive Cu-binding motif. Yet His2 is intrinsically vulnerable to UV-induced degradation, highlighting the need for stabilizing partners. In contrast, Tyr2 exhibits remarkable photostability and preferentially binds Cu(II) through its N-terminal, consistent with a second-shell protective role analogous to those observed in modern Cu-binding proteins. Together, these findings suggest that Earth’s UV-rich environment favored cooperative copper-binding dipeptides, where His₂ provided catalytic functionality while Tyr2 contributed photostability, establishing a plausible pathway from simple Cu-peptide complexes to functional metalloenzymes.
Shi et al. (Sun,) studied this question.