A new implicit solvent model for protein-ligand docking

Abstract

A new implicit solvent model for computing the electrostatics binding free energy in protein-ligand docking is proposed. The new method is based on an adaptation of the screening coulombic potentials proposed originally by Hassan et al. (J Phys Chem B 2000;104:6490-6498). In essence, it relies on two basic assumptions; (i) solvent screening can be accounted for by means of radially dependent sigmoidal dielectric functions and; (ii) the effective atom Born radii can be expressed only as a function of the exposed atom surface. Parameters of the model other than radii and charges are generic. These were optimized for a dataset of 826 protein-ligand complexes, comprising both X-ray complexes for 23 receptors as well as decoys generated by docking computations. We show that the new model provides satisfactory results when benchmarked against reference values based on the numerical solution of the Poisson equation, with a root mean square error of 4.2 kcal/mol over a range of approximately 40 kcal/mol in electrostatics binding free energies, a cross-validated r2 of 0.81, a slope of 0.97, and an intercept of 1.06 kcal/mol. We show that the model is appropriate for ligands of different sizes, polarities, overall charge, and chemical composition. Furthermore, not only the total value of the electrostatic contribution to the binding free energy, but also its components (coulombic term, receptor desolvation, and ligand desolvation) are reasonably well reproduced. Computation times of approximately 0.030 s per pose are obtained on a single processor desktop workstation.