As described elsewhere , six Boresch-style restraints (one distance restraint, two angle restraints, and three torsional restraints) were used to restrain the translation and orientation of the host molecule to impose a lab frame of reference. The translation was defined by restraints on anchor atoms D1-L1, D2-D1-L1, and D3-D2-D1-L1 while the orientation was defined by D1-H1-H2, D2-D1-H1-H2, and D1-H1-H2-H3. Collectively, these six restraints were referred to as "static" restraints because they are constant throughout entire simulations. The restraint free energy of the static restraints was not included in the calculation because the restraints do not alter the internal coordinates of the host molecule and thus do not contribute to the binding free energy and serve solely to define the frame of reference.