Next, we probed the ability of the GNNIS model to reproduce explicit-solvent MD simulations on an additional compound set I (Figure ) whose members were not part of the training set. Crucially, all compounds in set I can form intramolecular as well as solvent-intermediated hydrogen bonds and should thus be susceptible to solvent effects that are not simply correlated with the dielectric permittivity of the solvent. The free-energy profiles of the intramolecular hydrogen bonds (SI Figures ) and the free-energy differences ∆G between the global and the lowest-lying local minimum were calculated for both the GNNIS and explicit MD simulations. The comparison shown in Figure shows the excellent agreement between the approaches. Error bars indicating deviations below 0.5 kJ mol -1 are omitted for clarity. (C): Free-energy profiles of the formation of the intramolecular hydrogen bond of compound I1 simulated using explicit solvent (dashed lines) and the GNNIS model (solid lines). Low dielectric solvents are shown on the left: ethyl acetate, 1,4-dioxane, chloroform, and cyclohexane, high dielectric solvents on the right: DMSO, methanol, acetonitrile, and nitrobenzene. The color scale indicates the dielectric permittivity of the solvent. The free-energy difference ∆G between the global minimum and the lowest-lying local minimum for ethyl acetate is indicated by the red double arrow.