Molecular mechanisms of ion-specific effects on proteins

The specific binding sites of Hofmeister ions with an uncharged 600-residue elastin-like polypeptide, (VPGVG) ₁₂₀, were elucidated using a combination of NMR and thermodynamic measurements along with molecular dynamics simulations. It was found that the large soft anions such as SCN ^- and I ^- interact with the polypeptide backbone via a hybrid binding site that consists of the amide nitrogen and the adjacent α-carbon. The hydrocarbon groups at these sites bear a slight positive charge, which enhances anion binding without disrupting specific hydrogen bonds to water molecules. The hydrophobic side chains do not contribute significantly to anion binding or the corresponding salting-in behavior of the biopolymer. Cl ^- binds far more weakly to the amide nitrogen/α-carbon binding site, while SO ₄ ^2- is repelled from both the backbone and hydrophobic side chains of the polypeptide. The Na ⁺ counterions are also repelled from the polypeptide. The identification of these molecular-level binding sites provides new insights into the mechanism of peptide-anion interactions.