As discussed in Section 2.1.5, coupling thermodynamic perturbation with rotational move proposals can allow the ligand to cross energy barriers between binding modes while allowing some amount of relaxation to improve the acceptance of proposed moves. In our procedure (Figure ) interactions between the protein and ligand are on at the beginning of a move proposal. Then the interactions are turned off by scaling from 1 to 0 (where 1 corresponds to full interactions and 0 corresponds to no interactions) over a series of n steps, following the scheme shown in Figure . Soft core potentials were used to avoid numerical instabilities related to scaling the steric and electrostatic interactions, with a 1-1-6 potential with ↵ = 0.5. As the NCMC protocol progresses, we first turn off the electrostatics of the ligand by scaling its potential energy contribution linearly with lambda so that the electrostatics are completely removed as we go from = 0 to = 0.2. Then we decouple the Lennard-Jones interactions from = 0.2 to = 0.5 using soft core potentials so that the ligand is now fully noninteracting with the rest of the system (although its intramolecular Lennard-Jones interactions are still in place).