Implementing Protein-Polarized Ligand Charges into Relative Protein Ligand Binding Affinities Calculations

A major challenge in computer aided drug design is predicting relative binding energies of different molecules to a target protein using fast and accurate free-energy calculation methods. Free-energy calculations are primarily computed by utilizing classical molecular dynamics simulations based on all-atom force fields (FF) to model the interactions in the system. Present standard classical all-atom FFs contain fixed partial charges on the atoms and hence electrostatic interactions are modeled between them. The parametrization process to determine these partial charges usually relies on quantum mechanics or semi-empirical calculations of the molecule in the gas phase or homogenous water surrounding. These present standard parametrization schemes of the partial charges neglect, therefore, polarization effects from the protein surrounding. The absence of protein polarization effects can lead to significant errors in free energy calculations in proteins. We present a parametrization scheme for the partial charges of ligands, named protein induced polarization (PIP) charges, which account for the electrostatic polarization due to the protein-surrounding. The scheme involves single-point quantum mechanics/molecular mechanics (QM/MM) calculations of the ligand charges in the protein/water surrounding. Using PIP ligand partial charges, we have calculated the relative binding free energies (RBFEs) of well-studied protein-ligand systems. We show here that RBFEs computed with PIP charges are either significantly improved or at least comparable to those computed with non-polarized standard GAFF charges. Overall, we present a simple-to-use parametrization scheme to include protein polarization in any type of binding free energy calculations. The parametrization scheme increases accuracy in RBFE calculations while it does not add significant computation time to standard parametrization procedures.