Center of mass (COM) -COM flat-bottom harmonic distance restraints are an alternative to orientational restraints and have been applied to binding free energy calculations. We performed calculations restraining the distance between the COM of the ligand and the COM of a protein side chain and compared the results of the two restraint approaches (see SI Table ). The dissipated work was higher in the COM-COM restraining protocol (3.8 kcal/mol in the reverse direction and 1.4 kcal/mol in the forward direction) compared to the one using Boresch-style restraints. With a single COM-COM distance restraint, the ligand can sample the sphere with the radius of that distance restraint which presumably caused the larger dissipation. These findings suggests that the Boresch-style restraints were not a major source for the dissipation seen in Figure .