Two different sets of compounds were chosen for the comparison with explicit-solvent reference simulations (Figure ): (i) compound set C with five small molecules with a molecular weight <500 Da that can be well sampled and whose conformers can be characterized based on two key dihedral angles, and (ii) compound set P with ten neutral compounds extracted from the Platinum dataset with molecular weights between 500 Da and 700 Da that feature 5-10 rotatable bonds. Due to the different size of the compounds, the procedure to generate the conformational ensembles varies slightly between the two sets. For compound set C, 5'120 initial conformers were generated and an RMSD threshold of 0.075 nm was used for pruning. For compound set P, 51'200 initial conformers were generated and an RMSD threshold of 0.15 nm was applied.