Salt Bridge in Aqueous Solution: Strong Structural Motifs but Weak Enthalpic Effect

Salt bridges are elementary motifs of protein secondary and tertiary structure and are commonly associated with structural driving force that increases stability. Often found on the interface to the solvent, they are highly susceptible to solvent–solute interactions, primarily with water but also with other cosolvents (especially ions). We have investigated the interplay of an Arginine–Aspartic acid salt bridge with simple salt ions in aqueous solution by means of molecular dynamics simulations. Besides structural and dynamical features at equilibrium, we have computed the mean force along the dissociation pathway of the salt bridge. We demonstrate that solvated ions influence the behavior of the salt bridge in a very specific and local way, namely the formation of tight ionic pairs Li(+)/Na(+)–Asp(−). Moreover, our findings show that the enthalpic relevance of the salt bridge is minor, regardless of the presence of solvated ions.