Free Energy Calculations of Ligand–Protein Binding

The binding free energy is the central quantity to evaluate a given ligandreceptor complex. Hence, accurate calculation or prediction of binding free energies is one of the most important tasks of computational drug discovery. The binding free energy is directly related to the work of bringing a ligand from an unbound state in solution to a bound state in complex with a receptor molecule. It is inuenced by direct interactions between ligand and receptor but also by the interaction of both binding partners with the surrounding solvent. Furthermore, changes in average conformation and of conformational uctuations of the binding partners also contribute to the binding free energy.