For the simulations, harmonic distance restraints (between the closest atom to the center of the host and the closest atom to the center of the guest from the initial geometries) were used to allow the guest to explore the cavity and different binding orientations since the binding mode of some guests were unknown. Restraints are needed to define the standard state and ensure the ligand remains near the host to avoid sampling problems. We chose harmonic center-of-mass restraints in particular to allow the ligand to sample alternate binding modes if needed. This may help reduce bias in free energy estimates if we start from an incorrect binding mode (especially in the cases where the binding mode is unknown).