The calculation of relative binding free energies is relatively easy in comparison. The bound ligands are confined to the binding site and only the small subset of atoms that differ between two ligands need to be perturbed. In contrast, absolute binding free energy calculations decouple the entire ligand, meaning it is in principle free to explore the whole simulation volume. Early work on the topic explored various ways of restraining the decoupled ligand and taking into account the resulting contribution to the free energy . The approach introduced by Boresch et al has emerged as a rigorous way to resolve this issue via orthonormal relative restraints between the ligand and the protein .