Ligand-Receptor Affinities Computed by an Adapted Linear Interaction Model for Continuum Electrostatics and by Protein Conformational Averaging

Accurate calculations of free energies involved in small-molecule binding to a receptor are challenging. Interactions between ligand, receptor, and solvent molecules have to be described precisely, and a large number of conformational microstates has to be sampled, particularly for ligand binding to a flexible protein. Linear interaction energy models are computationally efficient methods that have found considerable success in the prediction of binding free energies. Here, we parametrize a linear interaction model for implicit solvation with coefficients adapted by ligand and binding site relative polarities in order to predict ligand binding free energies. Results obtained for a diverse series of ligands suggest that the model has good predictive power and transferability. We also apply implicit ligand theory and propose approximations to average contributions of multiple ligand-receptor poses built from a protein conformational ensemble and find that exponential averages require proper energy discrimination between plausible binding poses and false-positives (i.e., decoys). The linear interaction model and the averaging procedures presented can be applied independently of each other and of the method used to obtain the receptor structural representation.