One of the more intriguing experimental observations regarding this system is that the constrained peptides have more favorable binding enthalpies than their corresponding flexible peptides, by 1.1 and 2.5 kcal/mol , as listed in the first two rows of Table . In contrast, the calculations assign both flexible peptides more favorable binding enthalpies, by 1.3 and 5.4 kcal/mol (∆∆H in Table ), relative to their corresponding constrained peptides. This deviation between calculation and experiment holds across both peptide sequences. In addition, they are substantial on the scale of the experimental and computational uncertainties, particularly for cV and fV, where calculation deviates from experiment by nearly 8 kcal/mol. The fact that the flexible ligands bind more favorably in these calculations traces in part to the fact that they make more favorable contacts with the protein binding site, by over 20 kcal/mol, as evident from the values of ∆∆u inter in Table . In addition, the internal energy of the binding site is more favorable when the flexible ligands are bound, relative to the constrained ligands, as evident from the values of ∆u B in Table . Presumably, the flexible ligands can form more intimate interactions, and allow the binding site to adopt a more relaxed conformational ensemble, than the more rigid constrained ones. Indeed, the flexible ligands maintain their crystallographic interactions with the binding site during more of the simulations than do the constrained ligands. This is shown in Figure , which depicts the native contacts present for greater than 50% of each complex simulation. The flexible ligands maintain multiple native contacts (Fig. and), with many formed between the central residue of the ligand (Val or Glu) and the protein backbone (His107, Phe108, Lys109); the corresponding contacts are poorly maintained by the constrained ligands (Fig. and).