As a terse representation of a GAFF-like force field, SMIRNOFF99Frosst performs remarkably well. Despite having far fewer parameters than GAFF v1.7 and GAFF v2.1, SMIRNOFF99Frosst performs as well as GAFF v1.7 and arguably better than GAFF v2.1 on estimated binding free energies of small molecules to αCD and βCD, based on the mean signed error relative to experiment. Moreover, SMIRNOFF99Frosst performs better than either GAFF v1.7 or GAFF v2.1 on predicted binding enthalpies, with a mean signed error less than 1 kcal/mol. It should be noted that the binding free energy and enthalpy root mean squared errors (RMSE) and mean signed errors (MSE) for GAFF v2.1 are not substantially worse than those of SMIRNOFF99Frosst, and GAFF v2.1 has statistically significant better correlations with the the experimental data. GAFF v2.1 has excellent agreement with experiment on predicted binding entropy, followed by SMIRNOFF99Frosst and then GAFF v1.7. Taken together, these results support the notion that a force field with many fewer parameters can provide competitive performance. The reduction in the number of parameters, and the simplification of the force field specification, will make it easier to iteratively refine and optimize SMIRNOFF99Frosst against experimental data and the results of quantum mechanical calculations. However, both SMIRNOFF99Frosst and GAFF v1.7 result in excessively flexible representations of the cyclodextrin hosts, as detailed below. Cézard, et al. present strong NMR evidence that the vicinal 3 J H5-H6′ (atom names H5-H62 in Figure ) and 3 J H5-H6″(atom names H5-H61) coupling show minimal fluctuation in distance over a number of timescales, suggesting little change in the population of rotamers . This is also evident in X-ray structures, where the rigidity of the cyclodextrin ring is retained as long as water is present in the cavity and the torsional angles between adjacent glucose units show little variance (0.3-0.6°) across different crystal structures . The combination of X-ray and NMR data suggest that the specialized q4md-CD force field, and the rigid GAFF v2.1 force field, better model the flexibility of the CD cavity. The CHARMM36 force field displays similar structural dynamics to q4md-CD, with certain GROMOS force fields even more rigid than those . The present results suggest that, as SMIRNOFF99Frosst is further developed, it will be important to include sugars and other carbohydrates in the training sets used to develop parameters. Unfortunately, it may be challenging to find the types of high quality experimental data typically used to train force fields-heats of vaporization, heats of mixing, hydration free energies, and partition coefficients, among others-for biologically relevant sugars. Proper accounting of sugars, and protein-sugar interactions, will be especially useful for modeling physiologically relevant protein structures, such as proteoglycans and glycopeptides.