Anion Binding to Hydrophobic Concavity Is Central to the Salting-in Effects of Hofmeister Chaotropes

For over 120 years it has been appreciated that certain salts (kosmotropes) cause the precipitation of proteins, while others (chaotropes) increase their solubility. The cause of this Hofmeister effect is still unclear, especially with the original concept that kosmotropic anions make water structure and chaotropes break it being countered by recent studies suggesting otherwise. Here, we present the first direct evidence that chaotropic anions have an affinity for hydrophobic concavity and that it is competition between a convex hydrophobe and the anion for a binding site that leads to the apparent weakening of the hydrophobic effect by chaotropes. In combination, these results suggest that chaotropes primarily induce protein solubilization by direct binding to concavity in the molten globule state of a protein.