Host-guest systems, such as β-cyclodextrin (βCD), are convenient and tractable complexes that are often used to test new simulation methods, and notably exhibit many of the same characteristics as fragment binding to proteins. Owing to their small size, simulations of host-guest systems generally converge quickly. It has been reported that guests with a single polar group bind to βCD in two distinct orientations with the polar group pointing out of each end of the host, with ligands binding more favorably in the secondary alcohol orientation (Fig. ). To check if these binding modes are observed in our GCNCMC simulations, we pull frames from titration studies (Sec. 2.4) for two representative fragments, benzonitrile (Fig. ) and para-cresol (Fig. ). Specifically, we look at simulations with B values that gave approximately a 50% occupancy (B 50 ), as these are the B values corresponding to the dissociation constant, K D (see "Methods"). We overlay these frames and see that the polar group for both ligands, as expected, favorably points out the wider secondary alcohol opening of βCD (Fig. ).