All simulations were run at a constant temperature of 298.15 K using a Langevin thermostat with collision frequency 1.0 -1 and the pressure is maintained at 1 atm using the Monte Carlo barostat . All systems were minimized up to a maximum of 5000 steps and equilibrated in the NPT ensemble for 1 ns. Production simulations (in the NPT ensemble) were run up to 30 ns per window. The non-bonded interactions were truncated with a 9.0 Å cutoff. Long-range electrostatic interactions were handled with the particle mesh Ewald (PME) method while an isotropic dispersion correction was used for the long-range van der Waals interactions. The simulation time step was set to 4 fs with Hydrogen Mass Repartitioning (HMR). Free energy quantities were estimated with thermodynamic integration (TI) and/or the Multistate Bennett Acceptance Ratio (MBAR) method. The uncertainties for TI calculations were obtained using block analysis . CB8 guests G1 through G7 have a titratable nitrogen (Figure two simulations for CB8 with Ketamine (G5) were initially done. For guests G1-G4, and G6-G7, we initially did our calculations only on states with a protonated nitrogen, as these had populations of over 90% (Figures S1 through S7).