Specific Ion Effects on an Oligopeptide: Bidentate Binding Matters for the Guanidinium Cation

Ion-protein interactions are important for protein function, yet challenging to rationalize owing to the multitude of possible ion-protein interactions. To explore specific ion effects on protein binding sites, we investigate the interaction of different salts with the zwitterionic peptide triglycine in solution. Dielectric spectroscopy shows that salts affect the peptide's reorientational dynamics, with a more pronounced effect for denaturing cations (Li⁺ , guanidinium (Gdm⁺ )) and anions (I^- , SCN^- ) than for weakly denaturing ones (K⁺ , Cl^- ). The effects of Gdm⁺ and Li⁺ were found to be comparable. Molecular dynamics simulations confirm the enhanced binding of Gdm⁺ and Li⁺ to triglycine, yet with a different binding geometry: While Li⁺ predominantly binds to the C-terminal carboxylate group, bidentate binding to the terminus and the nearest amide is particularly important for Gdm⁺ . This bidentate binding markedly affects peptide conformation, and may help to explain the high denaturation activity of Gdm⁺ salts.