Evaluation of protein‐ligand binding free energy focused on its entropic components

Abstract The binding free energy for FK506‐binding protein‐ligand systems is evaluated as a sum of two entropic components, the water‐entropy gain, and the configurational‐entropy loss for the protein and ligand molecules upon the binding. The two entropic components are calculated using morphometric thermodynamics combined with a statistical‐mechanical theory for molecular liquids and the normal mode analysis, respectively. We find that there is an excellent correlation between the calculated and experimental values of the binding free energy. This result is compared with those of several other binding‐free energy calculation methods, including MM‐PB/SA. The binding can well be elucidated by competition of the two entropic components. Upon the protein‐ligand binding, the total volume available to the translational displacement of the coexisting water molecules increases, leading to an increase in the number of accessible configurations of the water. The water‐entropy gain, by which the binding is driven, originates primarily from this effect. This study sheds new light on the theoretical prediction of the protein‐ligand binding free energy. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011