Polarizability Plays a Decisive Role in Modulating Association Between Molecular Cations and Anions

Abstract: Electrostatic interactions involving proteins depend not just on the ionic charges involved but also on their chemical identities. Here we examine the origins of incompletely understood differences in the strength of association of different pairs of monovalent molecular ions that are relevant to protein-protein and protein-ligand interactions. Cationic analogues of the basic amino acid side chains are simulated along with oxyanionic analogues of cation-exchange (CEX) ligands and acidic amino acids. Experimentally observed association trends with respect to the cations, but not anions, are captured by a non-polarizable model. A polarizable model proves decisive in capturing experimentally-suggested trends with respect to both cations and anions. Crucially, relative to a non-polarizable model, polarizability changes the free energy surface for ion-pair association, altering configurational sampling itself. An effective continuum correction to account for electronic polarizability can also capture the experimentally-suggested trends, but at the expense of fidelity to the underlying free energy surface.