As illustrated in Figure and summarized in Tables and, for the COD small molecule crystal structures, the CREST/GFN2 method has a higher fraction of molecules within RMSD of 0.2 Å and 0.5 Å, compared to ETKDG, and a smaller median RMSD. Such performance arises mostly from molecules up to 3-4 rotatable bonds. The improved treatment of non-bonded interactions and electrostatics in the quantum GFN2 method likely gives rise to these geometries more closely matching experimental crystallographic geometries. Note, however, that for the Platinum set, derived from bound PDB ligands, performance of the CREST ensembles is generally worse than ETKDG, with worse median and mean RMSD, and considerably higher RMSD growing with the number of rotatable bonds, illustrated in Figure . We speculate that this difference derives from comparing gas-phase CREST/GFN2 conformers with bound ligand geometries, which may be more stabilized in extended conformations due to intermolecular interactions with a binding site and solvent. While there is a wide distribution of the calculated radius of gyration between the lowestenergy CREST/GFN2 generated conformations and the experimental crystal structures from COD and Platinum sets (Figure ), as compiled in Figure , the median radius of gyration for experimental COD and CREST-generated conformers are relatively close, (e.g., the ratio of the two is usually close to 1.0, Figure ). On the other hand, the Platinum crystallographic geometries show a notably larger radius of gyration than the CREST conformer (e.g., Figure ), with the deviation growing as a function of the number of rotatable bonds. Overall, the results indicate that CREST-derived conformer ensembles perform comparable to ETKDG ensembles on the small molecule COD set, with the caveat of a potential bias towards compact conformations relative to the Platinum bound PDB ligands, likely due to a neglect of intermolecular interactions in the gas-phase geometries.