Quantifying the Strength of a Salt Bridge by Neutron Scattering and Molecular Dynamics

The molecular structure and strength of a model salt bridge between a guanidinium cation as the charged side chain group of arginine and the carboxylic group of acetate in an aqueous solutions is characterized by a combination of neutron diffraction with isotopic substitution and molecular dynamics simulations. Being able to recover the second order difference signal, the present neutron scattering experiments provide direct information about ion pairing in the investigated solution. At the same time, these measurements serve as benchmarks for assessing the quality of the force field employed in the simulation. We show that a standard non-polarizable force field, which tends to overestimate the strength of salt bridges, does not reproduce the structural features from neutron scattering pertinent to ion pairing. In contrast, a quantitative agreement with experiment is obtained when electronic polarization effects are accounted for in a mean-field way via charge scaling. Such simulations are then used to quantify the weak character of a fully hydrated salt bridge. Finally, on top of the canonical hydrogen-bonding binding mode between guanidinium and acetate, these simulations also point to another interaction motif involving an out-of-plane hydrophobic contact of the methyl group of acetate with the guanidinium cation.