Optimal Dielectric Boundary for Binding Free Energy Estimates in the Implicit Solvent

Accuracy of binding free energy calculations utilizing implicit solvent models is critically affected by parameters of the underlying dielectric boundary, specifically the atomic and water probe radii. Here, a multidimensional optimization pipeline is used to find optimal atomic radii specifically for binding calculations in the implicit solvent. To reduce over-fitting, the optimization target includes separate, weighted contributions from both binding and hydration free energies. The resulting 5-parameter radii set, OPTBIND5D, is evaluated against experiment for binding free energies of 20 host- guest (H-G) systems, unrelated to the types of structures used in the training. The resulting accuracy for this H-G test set (Root Mean Square Error (RMSE) of 2.03 kcal/mol, Mean Signed Error (MSE) of -0.13 kcal/mol, Mean Absolute Error (MAE) of 1.68 kcal/mol, and a correlation of r=0.79 with the experimental values) is on par with what can be expected from the fixed charge explicit solvent models. Best agreement with experiment is achieved when the implicit salt concentration is set equal or close to the experimental conditions.