Optimal Dielectric\nBoundary for Binding Free Energy\nEstimates in the Implicit Solvent

Accuracy of binding free energy calculations utilizing\nimplicit\nsolvent models is critically affected by parameters of the underlying\ndielectric boundary, specifically, the atomic and water probe radii.\nHere, a multidimensional optimization pipeline is used to find optimal\natomic radii, specifically for binding calculations in the implicit\nsolvent. To reduce overfitting, the optimization target includes separate,\nweighted contributions from both binding and hydration free energies.\nThe resulting five-parameter radii set, OPT_BIND5D, is evaluated against\nexperiment for binding free energies of 20 host–guest (H–G)\nsystems, unrelated to the types of structures used in the training.\nThe resulting accuracy for this H–G test set (root mean square\nerror of 2.03 kcal/mol, mean signed error of −0.13 kcal/mol,\nmean absolute error of 1.68 kcal/mol, and Pearson’s correlation\nof <i>r</i> = 0.79 with the experimental values) is on par\nwith what can be expected from the fixed charge explicit solvent models.\nBest agreement with the experiment is achieved when the implicit salt\nconcentration is set equal or close to the experimental conditions.