For the M-Rig calculations, strong intermolecular restraints were used and therefore strong intramolecular restraints were also required. The large value of ∆G Preorg. which resulted from the strong intermolecular restraints allowed us to show that that intramolecular rigidification eliminates this error, by comparison of M-Rig and M-Rig-N. However, the strong intermolecular restraints resulted in a significant additional computational cost during the rigidification stage. The λ protocols for the rigidification stages could likely have been optimised to reduce the total number of windows to approximately 25 (Section S17), but this would still result in an additional computational cost comparable to the vanishing stage. Hence, we would not recommend multiple distance restraints with intramolecular rigidification when using strong intermolecular restraints. Instead, this scheme is expected to perform best with more permissive intermolecular restraints. An efficient implementation may be as follows: