Anions and Cations Affect Amino Acid Dissociation Equilibria via Distinct Mechanisms

Salts reduce the pK_a of weak acids by a mechanism sensitive to ion identity and concentration via charge screening of the deprotonated state. In this study, we utilize constant pH molecular dynamics simulations to understand the molecular mechanism behind the salt-dependent dissociation of aspartic acid (Asp). We calculate the pK_a of Asp in the presence of a monovalent salt and investigate Hofmeister ion effects by systematically varying the ionic radii. We observe that increasing the anion size leads to a monotonic decrease in Asp pK_a. Conversely, the cation size affects the pK_a nonmonotonically, interpretable in the context of the law of matching water affinity. The net effect of salt on Asp acidity is governed by an interplay of solvation and competing ion interactions. The proposed mechanism is rather general and can be applicable to several problems in Hofmeister ion chemistry, such as pH effects on protein stability and soft matter interfaces.