Interaction between Metal Cation and Unnatural Peptide Backbone Mediated by Polarized Water Molecules: Study of Infrared Spectroscopy and Computations

In this work, the interaction between metal cation and a model β-peptide <i>N</i>-ethylpropionamide (NEPA) in aqueous solution is investigated using infrared absorption spectroscopy. Monovalent (Na⁺), divalent (Ca²⁺, Mg²⁺), and trivalent (Al³⁺) metal cations added to NEPA/water solution at moderate concentrations split the amide-I frequency into a red- and blue-shifted component. Molecular dynamics simulations of NEPA in moderate cationic strength are conducted to gain insight into the structural details of the peptide–salt–water system, particularly in the vicinity of the amide group. Our results do not suggest a direct contact between cation and amide oxygen in the solution phase; otherwise, only a significant red shift in the amide-I frequency would occur due to the vibrational Stark effect, as evidenced by quantum chemistry computations. Instead, our results suggest it is the dynamical interaction between the formed cation/water/anion complexes and the amide group that causes the observed split in the amide-I peak, which indicates the presence of both salting-in (red-shifted) and salting-out (blue-shifted) NEPA species. The presence of dynamic and polarized water molecules between the amide oxygen and the cation complex is believed to be the key to the split amide-I peaks in the cation-rich environment. Our results can be useful to better understand the cationic Hofmeister series