Subtracting the component energies ∆∆u inter , ∆u B , and ∆∆u L , from the relative binding enthalpies, ∆∆H, yields ∆∆u other , the contribution of the solvent and the remainder of the protein, which includes their interactions with the ligand and binding site, to the overall relative binding enthalpies. This "other" contribution strongly favors binding of the constrained ligands (Table ), and, indeed, nearly cancels the contributions of the other components. Intuitively, the formation of favorable interactions between the ligands and the binding site, and within the binding site, is largely balanced by losses in favorable interactions involving the solvent and the rest of the protein.