Another alternative to Boresch restraints is to restrain the distance between multiple receptor-ligand atom pairs. These restraints offer several advantages; for example, they can be intuitively selected to match native receptor-ligand interactions such as hydrogen bonds, thus closely mimicking the interacting state. This may accelerate convergence by tightly restricting ligand motion while intermolecular interactions are removed. Furthermore, these restraints do not suffer from the numerical instabilities inherent to the Boresch restraints scheme. Indeed, multiple distance restraints were used in an early study of the binding of biotin to streptavidin. However, the naïve application of multiple distance restraints is theoretically incorrect, because they introduce coupling between the internal and external degrees of freedom of the protein and ligand, preventing the rigorous calculation of the free energy of releasing the non-interacting ligand. Despite this, a recent implementation has been described which relied on the assumption that the restraints were sufficiently weak that such coupling was negligible, and that the free energy of turning on the restraints was close to zero. However, this was not verified, and the scheme has not been systematically compared to Boresch restraints.