After excluding these outliers, the ddE energy histograms for datasets (i) and (ii) are shown in Figure and Figure , respectively. In Seaborn density histograms, bin height is normalized so that the total area of the histogram is 1 and the unity of density is 1/kcal mol -1 for ddE (whereas forRMSD plots it is 1/ Å). OPLS4 results were generated with the ffld server tool, not macromodel as in previous work, (see section Methods and Supporting Information for more details). OPLS4 could not be calculated for the proprietary dataset (ii) because that force field was not available in house for some of the industry collaborators in this study. The difference between MM relative conformer energies and QM relative conformer energies exhibits very similar distributions for all force fields. All distributions appear asymmetric, having a skew towards more negative ddE values than positive ones, indicating that the conformer energy differences may be underpredicted by MM compared to QM. In (i) the comparison between OPLS4, OpenFF-2.0.0 and GAFF-2.11 shows that the qualitative ordering of force fields from lowest to highest agreement with QM energies goes as GAFF-2.11 < OpenFF-2.0.0 < OPLS4 DEF < OPLS4 CST . In other words, the peak size around ddE = 0 kcal/mol (the fraction of conformations with good agreement between QM and MM relative energies) is greatest for OPLS4 CST , closely followed by OPLS4 DEF , then by OpenFF-2.0.0 and GAFF-2.11. OPLS4 CST and OPLS4 DEF predict 51.2 ± 0.4% and 47.9 ± 0.4% of conformers within 1 kcal/mol of QM, respectively. OpenFF-2.0.0 predicts 41.0 ± 0.4% and GAFF-2.11 37.6 ± 0.4% (standard error with 95% CI calculated with 2000 bootstrap iterations).