Alternative restraint schemes have recently been proposed to address these issues; Fu et al. proposed a method in which the restrained six external DoF are derived by finding the optimal rotation of the ligand which minimises its root-mean-square deviation (RMSD) with respect to a protein-ligand complex reference structure (after correcting for rotation and translation of the protein). By moving away from the six anchor points of the VBA, this was intended to simplify the selection of stable and efficient restraints. The "distance to bound configuration" (DBC) restraint is also intended to simplify restraint selection and to minimise the variance of free energy estimates for removing the ligand's intermolecular interactions. This is achieved by directly restraining the RMSD of a subset of the ligand coordinates within the frame of reference of the binding site in order to optimally restrict the accessible configurational volume as the ligand intermolecular interactions are removed. However, because this scheme couples the internal and external degrees of freedom of the protein and ligand, there is no simple way to calculate the free energy of releasing the noninteracting ligand to the standard state. This necessitates a final stage to release the DBC restraints to a single harmonic restraint, for which the free energy of release is simple to calculate.