When combining MolDarting with BLUES, an additional step is added to the MolDarting procedure. We found that these restraints were needed because when the ligand steric interactions are diminished, it is more labile inside the binding pocket and can frequently end up outside the darts. To reduce the lability of the ligand, an orientational restraint, also known as a Boresch-style restraint is applied to the first three ligand Z-matrix atoms, relative to three reference atoms in the protein. This restraint restricts the orientation relative to the binding site via restricting one distance, two angles and three torsions, and involves three reference atoms in the ligand and three in the receptor. Here, we scale this restraint with the lambda parameter that controls the electrostatics and sterics; when the ligand is fully non-interacting, the restraints are in full effect (Figure ). To maintain detailed balance when applying restraints, before the NCMC move occurs the we check if the ligand is currently within a dart; if it is then the orientational restraints associated with that pose will be turned on over the first half of the NCMC move. If the ligand is not within the same dart as at the start of the move, then the move is rejected.