An Implicit Solvation Model for Binding Free Energy Estimation in Nonaqueous Solution.

Abstract

Implicit solvation models permit the approximate description of solute-solvent interactions, where water is the most often considered solvent due to its relevance in biological systems. The use of other solvents is less common but is relevant for applications such as in nuclear magnetic resonance (NMR) or chromatography. As an example, chloroform is commonly used in anisotropic NMR to measure residual dipolar couplings (RDCs) of chiral analytes weakly aligned by an alignment medium. They can be calculated from molecular dynamics (MD) simulations with explicit solvent, but it is computationally expensive, because tens of microseconds-long MD trajectories should be collected. Here, we develop a computational protocol and numerical implementation for binding free energies of rigid organic molecules to poly-γ-benzyl-l-glutamate using an implicit solvation model of chloroform. The model parameters are fit to alchemical binding free energies obtained from MD simulations in explicit chloroform and compared to the MD results and another implicit solvation model. Possible applications of the method are docking or Monte Carlo simulations based on a physically meaningful scoring function for the fast prediction of interaction poses of ligands for selective binding or the alignment of analytes.