where R, RL, and L correspond to receptor-receptor, receptor-ligand and ligand intramolecular interactions, respectively. The second term acts as the coupling term between the ML and MM subsystems and consists of the standard Coulomb and Lennard-Jones 12-6 nonbonded interaction energies. Thus, a general force field (here, GAFF2 or Parsley) is still required for the ligand to model the non-bonded interactions with the receptor. The use of ANI helps to avoid known deficiencies in the potential energy surfaces predicted by force fields, while ensuring that the optimisations are significantly faster than could be achieved with full quantum mechanics. For example, it has been shown that the description of biaryl torsions, which are commonly found in drug-like molecules, is one area where ANI2x performs better than contemporary general force fields. The hybrid ML/MM approach has also been shown to predict binding poses that overlap well with crystallographic electron density maps of bound ligands, even for those that contain charged moieties that were not included in the training of the ANI potential. As such, in FEgrow, users may turn on the hybrid approach for binding pose refinement provided the molecule contains only elements covered by the model (H, C, N, O, F, S, Cl), else the selected classical force field is used for the entire ligand.