For this challenge we hoped participants would submit multiple methods which varied by only changing a single simulation parameter, such as a force field or an aspect of the simulation protocol, since such variations would allow us to directly probe the sensitivity of results to particular choices. Thus for our reference calculations the goal was to compare and test different force fields. At the same time, several protonation states needed to be considered for one guest. In particular, ketamine (G5), since its pKa value was near the experimental pH of 7.4. However, it was possible that alternative protonation states were accessible for other guests, thus necessitating their consideration. In such cases, close attention to the geometry of certain trivalent nitrogen centers would be required because if protonated, computationally they can act as a chiral center and all guest geometries might need to be sampled. If geometric sampling is inadequate, the selected geometry may impact the binding estimates for some methods. The 3D ball and stick figures are of TEMOA on the left and TEETOA on the right; (bottom) guests G1-G5. The difference between the hosts is the functionality near the cavity opening, TEMOA has four methyl groups while TEETOA has four ethyl groups. The guests for SAMPL8 are named G1 -G5. Guests are fairly rigid molecules with carboxylate and/or hydroxyl groups. For TEMOA-G3, binding free energies were previously reported, thus was made optional for participants.