Correcting electrostatic artifacts due to net‐charge changes in the calculation of ligand binding free energies

Abstract

Alchemically derived free energies are artifacted when the perturbed moiety has a nonzero net charge. The source of the artifacts lies in the effective treatment of the electrostatic interactions within and between the perturbed atoms and remaining (partial) charges in the simulated system. To treat the electrostatic interactions effectively, lattice-summation (LS) methods or cutoff schemes in combination with a reaction-field contribution are usually employed. Both methods render the charging component of the calculated free energies sensitive to essential parameters of the system like the cutoff radius or the box side lengths. Here, we discuss the results of three previously published studies of ligand binding. These studies presented estimates of binding free energies that were artifacted due to the charged nature of the ligands. We show that the size of the artifacts can be efficiently calculated and raw simulation data can be corrected. We compare the corrected results with experimental estimates and nonartifacted estimates from path-sampling methods. Although the employed correction scheme involves computationally demanding continuum-electrostatics calculations, we show that the correction estimate can be deduced from a small sample of configurations rather than from the entire ensemble. This observation makes the calculations of correction terms feasible for complex biological systems. To show the general applicability of the proposed procedure, we also present results where the correction scheme was used to correct independent free energies obtained from simulations employing a cutoff scheme or LS electrostatics. In this work, we give practical guidelines on how to apply the appropriate corrections easily.