Dependence of Binding Free Energies between RNA Nucleobases and Protein Side Chains on Local Dielectric Properties

In order to fully understand the microscopic origins of binding specificity between nucleic acids and proteins, it is imperative to study the dependence of the binding preferences between nucleobases and protein side chains on the properties of the environment. Here, we employ molecular dynamics simulations and umbrella sampling to derive the potentials of mean force and the associated absolute binding free energies between the four standard RNA nucleobases and the side chains of aspartic acid and tryptophan in water/methanol mixtures exhibiting a wide range of dielectric constants. In addition to their opposing character when it comes to hydrophobicity, aspartate and tryptophan side chains were chosen because they exhibit the greatest change in binding free energies with nucleobases between pure water and methanol environments. We exploit a strong linear dependence of the derived ΔG values on the mole fraction of methanol to estimate the binding free energies of all possible combinations of different sta...