One common theme we observe after several iterations of SAMPL is that predictions for cavitands are typically more accurate, while cucurbiturils and cucurbituril-like hosts (including clips) are more challenging. Key modeling difficulties for the hosts studied in SAMPL8 have been highlighted previously as noted above, and are discussed here briefly. Host binding sites with tight entry portals can have barriers preventing entry or exit of guests with bulky cores. This can limit and hinder sampling of guests and lead to convergence problems. Ensuring adequate host conformational sampling and guest sampling is needed for accurate binding free energy calculations. Slow motion of waters into and out of the cavity, with the number of water fluctuations occurring at timescales of over tens of nanoseconds has been shown to affect binding free energy predictions . The slow fluctuation of waters is thought to occur in the absence of strong binders. In addition, salt concentration and the buffer conditions may modulate binding, the hosts may bind ions which can compete with other ligands for the binding site, and affect the accuracy of the binding affinity predictions. Charged guests can pose methodological challenges and may introduce finite-size artifacts that need to be accounted for . The protonation states of the host and/or guest may be modified upon binding, and if there is a significant pKa shift of titratable groups, treating the wrong protonation state (or even only a single protonation state) may lead to large errors in binding free energy estimates .