The dataset used in this research was previously introduced by Kearns et al. in 2019 and contains 22 molecules that were identified as having high penalties by the CHARMM General Force Field (CGenFF), indicating that they contain substructures outside CGenFF's applicability domain. This dataset is referred to as the High Penalty set, and the topology and parameter sets are publicly available at . Four molecules were omitted from the analysis. In addition to three molecules for which there was a mismatch between the topology defined in the provided files and the ZINC SMILES string (hp1, hp6 and hp11), we were unable to perform stable simulations with molecule hp22 using the ANI-2x NNP. The sulfonate ester moiety that connects the sulfonate group and the oxygen atom displayed an unexpected bond break during the simulations. To our knowledge, this moiety is not a suitable leaving group, and this nonphysical behavior could indicate a potential issue with the NNP for this chemical group. Other molecules containing sulfur did not show similar behavior, and hp22 was the sole sulfonate compound in the dataset that we examined. The SMILES strings and ChEMBL-Ids of the HiPen molecules are shown in Table and the molecular structures can be seen in Figure . For each molecule in the dataset, 3D conformations were generated using the chemoinformatics software package rdkit (Version 2022.03.4). 50