where r is the distance between two atoms. The modification of the LJ parameters was implemented by adding new "scaled" ligand atom types. We multiplied the ϵ parameter of all original ligand atom types with a scaling factor γ to soften the potential. In this work we used a scaling factor of γ = 0.5, however, we found that in some cases it was necessary to further reduce the value to γ = 0.01 in some parts of the molecule in order to achieve sufficient sampling (see Section 5.3).