Previous studies of cucurbiturils, including CB7, have highlighted the importance of host and guest sampling, salt effects, and water model. Sampling of the CB7 host is thought to be straightforward because it is fairly rigid. However, guest binding modes might be challenging to adequately sample, especially for the more flexible guests. In the presence of buffer and/or salt, ions may compete with guests for the binding site. In addition, cationic guests could have interactions with counter-ions in solution, lowering affinity compared to zero-salt conditions . One previous study showed a 6.4-6.8 kcal/mol dependence on salt concentration . The water structure around CB7 is sensitive to the choice of water model, and water is important in modulating binding in SAMPL7 systems. The choice of water model is also likely to have an impact on the number of sodium ions that must be displaced upon host-guest binding. While these insights result from studies on CB7, some of them may carry over to the TrimerTrip host studied here. However, unlike its macrocyclic derivatives, TrimerTrip is acyclic and able to flex the methylene bridged glycoluril trimer backbone .