Understanding the Binding and Structures in Model Complexes of Polypeptides and Cofactors.

Competitive binding between metal cofactors and functional groups of polypeptides results in a diversity of structures and chemistries in metalloproteins. Herein, we examined elements of this competitive binding using [metal-(auxiliary ligand)-(peptide)] complexes, where the metal-(auxiliary ligand) combinations are Cu^II(terpy)²⁺, Co^III(salen)⁺, and Fe^III(salen)⁺ and the peptides are either the dipeptide arginine-tyrosine (RY) or the tripeptide arginine-tyrosine-glycine (RYG). Structural diversity was established and substantiated via tandem mass spectrometry, with and without peptide derivatization and substitution. All the complexes dissociated to give high abundances of the peptide radical cations, but the structures of these ions differ depending on the composition of the preceding metal complex. Density functional theory calculations provided insights into different binding modes within the complexes and also provided details of the mechanisms by which different [RY]^•+ and [RYG]^•+ ions fragment. Infrared multiple-photon dissociation spectroscopy established that [Cu-(terpy)-RYG]²⁺ is bound through the carboxylate group, but calculations showed that it can convert to the phenolate-bound structure under a low-energy barrier. Despite the variety and apparent complexity in binding, the overall chemistry could be characterized using intrinsic acid-base chemistry and the concept of hard/soft Lewis acids/bases. The resulting complex structures were experimentally probed and were found to be in accordance with predictions. For the complexes, the drive toward energy minimization can take several pathways that involve multiple functional groups, thereby leading to a rich chemistry.