The accuracy of conformational ensembles generated with conventional implicit solvent models has been limited by their deficiencies in the description of explicit solvent effects (e.g., relative stability of intramolecular hydrogen bonds, see SI Figures ). On the other hand, the GNNIS model does, as shown above, accurately reproduce such explicit solvent effects. We have further explored this approach for rapid identification of Boltzmann-weighted conformational ensembles of small molecules. The procedure used is depicted in Figure (see Methods section for more details). Briefly, a diverse set of random conformers is generated using distance geometry and minimized using a standard force field (OpenFF 2.0.0 ) in combination with the GNNIS model. The resulting ensemble is sorted based on the potential energy of each conformer and pruned based on the root-mean-square distance (RMSD). In the last step, the free energies of the final conformers are estimated using Grimme's quasi-RRHO approach . Values of the two dihedral angles around the amide bond of C1 are represented as black dots for the various conformers. The reference free-energy profile is depicted by the blue heatmap. From left to right, the steps in the workflow include: (1) generating random conformers (here with KDG ), (ii) minimizing these conformers using OpenFF for the intramolecular interactions combined with the GNNIS model, (iii) sorting conformers by their potential energy, (iv) RMSD pruning of the ensemble, and (v) estimating free energies. (B): Comparison of the estimated free energy of the final set of conformers with the free energy computed from the explicit-solvent reference simulation for C1 in water. Dashed lines indicate a difference of 1 k B T from the identity line. (C): Comparison of the conformer ensembles minimized in vacuum, using GB-Neck2, or using the GNNIS model for compound set C (left) and P (right). Models are compared based on the balanced accuracy score of finding conformers below 1 k B T. The sampling error of the explicit-solvent simulation is given for reference. Statistically significant differences (p < 0.05) between a model and the model to its left are indicated by a star. The median balanced accuracy is indicated by the horizontal line.