The greater rigidity of the cyclodextrins when simulated with GAFF v2.1 may contribute to its tendency to generate greater binding affinities and more negative enthalpies than the other two force fields, as a more rigid host may avoid an energy penalty associated with flipping the glucose residues out of the binding cavity to accommodate a guest molecule. The better preorganized cavity might also relate to the uniformly higher correlations between calculation and experiment for GAFF v2.1. On the other hand, it is perhaps unexpected that this force field which best represents the conformational preferences of the cyclodextrin yields consistently too negative binding free energies and enthalpies. It is worth noting the magnitude of these effects will depend on the guest parameters, as well as water model and ion parameters as well.