The main flaw of multiple distance restraints is that, applied naïvely, they may couple the internal and external degrees of freedom of the receptor and ligand, preventing the simplification of Equation 4 to 5 and hence the calculation of ∆G o Release . Here we investigate three approaches to circumvent this difficulty (Figure ). The first is to implement multiple distance restraints in such a way that the error introduced is negligible (the "naïve" approach). This is the basis for recent implementations in the Michel group, in which sets of relatively permissive flat-bottomed restraints were used. An approximate value for