functional with the new D4 dispersion correction parameters and the def2-TZVP basis set in all DFT-D4 calculations. This functional/basis set combination has proven to be highly accurate in both our intermolecular interaction benchmarks using the S66x8 standard set and our study comparing calculated vacuum conformations to high-quality experimental geometries . I selected 1,600 successful results in vacuum and 1,610 in aqueous continuum for FDA-approved drugs, and 3,892 and 3,917 for natural compounds in vacuum and aqueous continuum, respectively. A small number of calculations showed unwanted behaviors, where the original bonds from the SDF file were altered during QM semi-empirical geometry optimizations. We excluded these cases since we are focusing on conformations of the same molecules in this project, not investigating tautomers or chemical reactions.