A comprehensive examination of the contributions to the binding entropy of protein-ligand complexes.

One of the most important requirements in computer-aided drug design is the ability to reliably evaluate the binding free energies. However, the process of ligand binding is very complex because of the intricacy of the interrelated processes that are difficult to predict and quantify. In fact, the deeper understanding of the origin of the observed binding free energies requires the ability to decompose these free energies to their contributions from different interactions. Furthermore, it is important to evaluate the relative entropic and enthalpic contributions to the overall free energy. Such an evaluation is useful for assessing temperature effects and exploring specialized options in enzyme design. Unfortunately, calculations of binding entropies have been much more challenging than calculations of binding free energies. This work is probably the first to present microscopic evaluation of all of the relevant components to the binding entropy, namely configurational, polar solvation, and hydrophobic entropies. All of these contributions are evaluated by the restraint release approach. The calculated results shed an interesting light on major compensation effects in both the solvation and hydrophobic effect and, despite some overestimate, can provide very useful insight. This study also helps in analyzing some problems with the widely used molecular mechanics/Poisson-Boltzmann surface area approach.