We estimate the ABFE, ∆G b , for host-guest complexes using the APR method as implemented in version 1.2.0 of the Python package pAPRika (), which is integrated into OpenFF-Evaluator. The protocol for the host-guest calculations is similar to that of an earlier study of cyclodextrin complexes. 12,14 Briefly, we apply Boresch-style restraints 2 on the host and guest molecules to restrain their translational and orientational motion. These restraints consist of bond, angle, and dihedral restraints that orient the host-guest complex to pull the guest molecule in the z-axis. To aid in defining the Boresch restraints, we include three noninteracting dummy atoms in each host-guest complex. Note that the Boresch restraints applied to the host molecule do not contribute to the binding free energy. We use a spring constant of 5 kcal/mol/ Å2 for bond restraint and 100 kcal/mol/rad 2 for the angle and dihedral restraints. The former is calculated over the same 15 windows as in the attach phase but in reverse and without the guest molecule. The latter is calculated analytically, including the standardstate correction at 1 M. For cyclodextrin complexes, we perform the APR calculations for two binding poses due to the asymmetry of the host molecules. The binding poses are defined by the orientation of the guest molecule with respect to the primary/secondary face of the cyclodextrin, and we combine the binding free energies of the two poses with