Often, coordinate generation and conformer tools are evaluated, in part, by comparing the ensemble of generated geometries against experimental crystallographic geometries. For example, the ETKDG method has proven to generate structures with small root mean square displacement (RMSD) when compared to small molecule crystal structures and bound ligand geometries. Consequently, our first comparison is between the CREST-generated GFN2 conformer ensembles and the ETKDG 250 conformer ensembles across the Crystallographic Open Database (COD) and Platinum diverse data sets. As noted above, while CREST attempts to generate exhaustive ensembles under 6 kcal/mol from the global minima, in general only a few conformers are generated (Figure -S6), and 250 conformers is sufficient to encompass 93% of the COD set and 85% of the Platinum diverse set (Figure ). While larger ensembles tend to yield smaller RMSD, a comparison is still useful despite some differences in ensemble size. Calculating the smallest non-hydrogen RMSD of each generated ensemble and the experimental crystal structure geometry (Fig. ), we find that the CREST ensembles perform better than ETKDG on molecules with few rotatable bonds (e.g., zero to ∼ 3 -4 rotors) on the COD set, comparable RMSD across a broader range of COD molecules, and slightly worse on the Platinum set (e.g. Figure ) and Table ). Note that the closest geometry to the experimental geometry is often not the lowest-energy CREST/GFN2 conformer.