Cyclodextrins, in particular, are ideal host molecules for testing computational methods. They are neutral across a broad pH range, with well-characterized structures , and bind both small molecule fragments and drug-like guest molecules with reasonable affinity, from near -1 kcal/mol to about -5 kcal/mol in the present work , and with higher affinity for some cyclodextrin derivatives . Moreover, cyclodextrins are stable in a wide range of experimental conditions and their high millimolar aqueous solubility allows a range of different experimental techniques to be used to measure their binding to guests . Here, we report the calculation of binding free energies, enthalpies, and entropies of small guest molecules with functional groups often found in drugs to α-and β-cyclodextrin host molecules, converged to within 0.1 kcal/mol statistical uncertainty, using the APR method. These calculations offer an opportunity to benchmark-and ultimately optimize-new and existing force fields.