To compare these, we first used the minimized ensemble to predict the free-energy difference between the two ketone rotations. Next, the difference between these predictions and their mean (∆∆G pre ) is compared to the experimentally determined free-energy differences and their mean (∆∆G exp ). The results are shown in Figure . Overall, the GNNIS model reproduces the differences with respect to the conformational ensembles in the different solvents very accurately, with most of the ∆∆G values within one k B T . This is especially interesting as this rotation, based on experimental findings, takes place on the µs timescale, making the analysis with explicit-solvent simulations extremely time-intensive. Comparing the results to GB-Neck2 simulations highlights the improvement over state-of-the-art conventional implicit solvent methods (see SI Figures ). Ensembles minimized with GB-Neck2 predict almost the same values for the different polar solvents and the strength of the solvent effect is significantly underestimated (i.e., the median slope is 0.43). The high accuracy and low computational effort suggest the GNNIS model is well suited to study these kinds of systems. Markers filled with grey represent measurements where the experiment could not determine the free-energy difference between the two rotations exactly. In these cases, the value indicated for these points provides an upper limit to the undefined values.