ANI-ML potential can stop earlier than the real minimum reached because of the nature of the non-smooth PES. We start with hydrogen fluoride, HF, a diatomic molecule with one of the simplest representations of PES (only on H-F distance) as an illustration of how ML-potentials can be non-smooth. Figure shows the potential energy profile of H-F distance calculated by G16 and ANI-2x. If one would perform geometry optimization of HF in which the initial structure of H-F distance is out of the 0.6-1.2 A range, the optimization with ANI-2x would fail due to saddle points near 0.5 and 1.9 A whereas G16 still brings the structure to the equilibrium distance of 0.96 A. Indeed, we have started at several different initial distances and observed convergence of energy at the saddle point in the case of LBFGS algorithm and ANI-2x calculator. Although it is not the case in this study, it should be noted that ANI is trained on neutral compounds and is not capable of accurately modeling spin states or charges that may arise when atomic distances exceed the bond dissociation limit. To better illustrate when the system is larger, we have also performed a two dimensional (the symmetric stretching and bending vibrational modes) scan the coordinates of H2O. Figure shows the non-smooth regions on PES generated by ANI-2x. It is apparent that when the structures are near equilibrium geometry, ANI-ML potentials work very well in terms of finding the nearest minimum. However, when the structure is far from equilibrium geometry (local minimum), ML potentials can be stuck at several non-smooth parts of multidimensional PES. Our next step with ANI is to assess it on several small compounds, in which there are only a few torsion points. Using When we used the manually generated conformations by rotating around the torsion points (i.e., including several intermediates at each torsion point), ANI based optimizations yield the same conformers predicted by QM calculations (Table ). This is as expected because we manually generated intermediate structures connecting each minimum and thus no conformer generation algorithm is required (i.e., DeepConf and Auto3D are the same at this point as ANI-2x).