Although it may be expected that a more rigid ligand will incur smaller losses in configurational entropy on binding, we see the opposite pattern: the constrained peptides lead to considerably more unfavorable changes in configurational entropy on binding than the flexible ones, by 7-8 kcal/mol, at least for the ligand and binding-site torsions considered here (Table , Sum). This result is consistent with the paradoxical experimental observation that the entropy of binding is less favorable for the constrained than the flexible ligands. (Note, however, that the experimental entropies account for the entire system, including the solvent; whereas the present results account only for a small number of ligand and binding-site torsions.) That the constrained ligands lead to more unfavorable changes in configurational entropy on binding traces primarily to the binding site torsions, rather than the ligands themselves: binding of the constrained ligands leads to about a 5 kcal/mol greater loss of configurational entropy in the binding site than does binding of the flexible peptides (Table , -T ∆S B,ij ). This is physically plausible, because a more rigid ligand may constrain the binding site more, as previously suggested .