According to the simulations, the flexible ligands make much more energetically favorable interactions with the binding site than do the constrained ligands, by on the order of 20 kcal/mol. In addition, the binding site residues are predicted to adopt conformations with a lower mean internal energy in the presence of the flexible ligands than with the constrained ones, by 4-10 kcal/mol. The experimental measurements cannot, of course, provide this level of granular detail. However, it is plausible on physical grounds that more flexible ligands should conform better to the binding site, and also allow the binding site residues to spend more time in their own preferred conformations. Thus, one may speculate that these trends in the component energies are qualitatively valid, and that the deviation of the overall relative enthalpies from experiment stems from an imbalance of these contributions with the counterbalancing contributions from solvent and the rest of the protein, as suggested above. Unfortunately, there is no possibility to compare these component terms with results from the prior simulation study of these systems , because it used a method which did not allow the enthalpy changes to be broken down by structural component.