In addition to the trypsin-benzamidine system, previous SEEKR studies have focused on computing the kinetics of a so-called "host-guest" model system, composed of the β-cyclodextrin and a series of small organic molecules. Using SEEKR2, as we did with MMVT SEEKR, we divided the space surrounding the β-cyclodextrin into twelve concentric spherical Voronoi cells (Figure ) and recomputed koff (Figure ), kon (Figure ), and ΔGbind values (Figure ) for the seven ligands mentioned in previous publications, both with and without HMR. SEEKR2, both with and without HMR, now correctly ranks the compounds by koff. SEEKR2 also represents a substantial improvement in the calculations of absolute kons for the host-guest system, although SEEKR2 does not correctly rank kons for all seven host-guest systems, which is difficult for any method since the host-guest kons differ by magnitudes that are relatively small compared to experimental margins of error. The ΔGbind values were computed with fairly similar accuracy to previous calculations, with the exception of aspirin, which showed an anomalous ΔGbind value. It is likely that the noise seen in the kon and ΔGbind calculations are primarily caused by the concentric spherical milestone shapes used in this study, which may not adequately approximate isosurfaces of the committor function for the host-guest system, as would be *10 required by exact milestoning theory. Additional milestone shapes have only been recently implemented in SEEKR2, which will allow us to investigate whether other types of milestones will improve the accuracy of kon calculations for the host-guest system. For each individual hostguest system, the cost of the SMD simulations to generate a starting structure was 110 ns, the MD MMVT ran for 700 ns each, as well as 110,000 BD trajectories per guest molecule. This is slightly longer than the ~560 ns total MD of our previous MMVT study. The reason for this is similar to the trypsin-benzamidine system above; the host-guest simulations in our previous study were halted after arbitrary times based on the satisfaction of a convergence metric. In this study, we elected to extend the simulations to 50 ns per anchor, for all host guest systems, in order to simplify and standardize the calculation. As with the trypsin-benzamidine system, using HMR to reduce simulation cost did not seem to adversely affect the host-guest resultsgenerating kinetics that were close to experimental values, albeit somewhat different from the results obtained using non-HMR simulations. It is likely that the differences between HMR and non-HMR results were primarily caused lack of convergence due to limited simulation time.