Quantifying the Thermodynamic Molecular Driving Forces in Protein-Ligand Binding

Abstract

The thermodynamic driving forces behind protein-ligand binding are still not well understood. To better understand these phenomena we calculate spatially resolved thermodynamic contributions of the different molecular degrees of freedom for the binding of propane and methanol to multiple pockets on the proteins Factor Xa and p38 MAP kinase, as examples. An end-point method grounded in statistical physics is presented to compute thermodynamic contributions of the bound and free states from canonical ensembles obtained from molecular dynamics simulations. Energetic and entropic contributions of water and ligand degrees of freedom provide an unprecedented level of detail into the mechanisms of binding. We found direct protein-ligand interaction energies to play a significant role in both non-polar and polar binding, which is comparable to water reorganization energy. For both solutes, the entropy of water reorganization is predicted to favor binding in agreement with the classical view of the “hydrophobic effect“, which is countered by ligand entropy. Depending on the specifics of the binding pocket, both energy-entropy compensation and reinforcement mechanisms are observed. Notable is the ability to visualize the spatial distribution of the thermodynamic contributions to binding at atomic resolution, opening up exciting avenues for mechanistic investigations of protein-ligand binding.