To calculate the correct potential of the binding site restraints, we exploited the translational and rotational invariance of the unrestrained stages to calculate the free energy associated with (only) the conformational rearrangement. We post-processed the trajectories of the unrestrained stages by aligning every frame of the trajectories onto the reference positions of the restraints used for the restrained stages. We then used these realigned positions of the unrestrained frames to evaluate the Hamiltonians of the origin-dependent stages. The Python code for post-processing the trajectories of the unrestrained stages, and for calculating the potentials of restraining the binding site can be found in the GitHub repository waterNES. The post-processing is necessary due to the choice of Cartesian position restraints over origin-independent restraints, such as, dihedral restraints or distance restraints between atoms. While we did experiment with originindependent restraints, we were unable to find a setup that would consistently avoid pocket collapse across all target proteins included in our test set. For example, using dihedral restraints on the residues of a binding site to avoid collapse would pose challenges in systems where the binding site is formed by two separate chains of the protein (for example, HIV-1 Protease). In such cases, the binding site could still collapse by a translation motion of the two protein chains, while the dihedral restraints would be still in place. The Cartesian position restraints, on the other hand, are extremely straightforward to set up and very effective at keeping the binding pocket open. We therefore think that the post-processing of the trajectories to calculate the correct potential of the origin-dependent restraints is a small price to pay for a simpler and more robust setup that favors automation. We chose the positional restraints on the heavy atoms of the binding site to be weak enough that they don't impair the dynamics of the system significantly. We selected the heavy atoms for the position restraints according to the procedure described in Supporting Document Section S1.3, and restrained each of the selected heavy atoms with a light force constant of 0.5 kcal mol -1 Å -2 .