The ML/MM framework is integrated into the extensible QM/MM SANDER interface, which allows the user to invoke an ML/MM simulation with ANI serving as the ML calculator. If the ANI-MBIS model is selected, the ML/MM coupling is performed within the embedding theory discussed above. The other ANI models (ANI-1x, ANI-2x, ANI-1cxx) only work at the mechanical embedding level, in which the atomic charges for the ML region are read from the topology file, and neither distortion nor polarization corrections are included.