1. Select flat-bottomed, rather than harmonic, intermolecular restraints and select the flat-bottomed regions so to include almost all distances sampled during the unrestrained simulation of the fully-interacting complex In cases where such flat-bottomed restraints are used, and there is little rearrangement of the ligand or binding site upon decoupling, ∆G Preorg. would be expected to converge immediately and the above scheme would reduce to the naïve multiple distance restraints scheme. When this is not the case, the naïve scheme would be expected to yield incorrect results, while the above scheme should remain correct.