Reference calculations were conducted using GAFF parameters and AM1-BCC charges. GAFF parameters and guest AM1-BCC charges were assigned using Antechamber, and AM1-BCC charges for the host were assigned using the OpenEye toolkits because Antechamber could not charge the hosts. The starting poses were determined by docking via AutoDock Vina and the top scoring pose was selected. If multiple orientations need to be considered, our Hamiltonian replica exchange based simulations, in theory, ought to sample them despite starting from a single orientation. A host-guest complex was manually created in tLeap and TIP3P was used to solvate the host-guest complex and the guest. In addition, sodium and chloride were manually added as counter ions, and additional ions were added to mimic experimental buffer conditions. Subsequently, AMBER restart, topology, and input coordinate files were generated with tLeap. The starting simulation files (AMBER restart/coordinate (rst7) and topology (prmtop)), workflow and methodology details, and yaml scripts (with protocol parameters) are available at SAMPL7 GitHub repository (see ).