In this context, it is noteworthy that predictions obtained with a classical force field and the GNNIS model also show excellent agreement with experiment as demonstrated in our previous study . However, the largest outlier in this study was molecular balance A3, which features a nitrile group in close proximity to a key hydrogen bond interacting with the ketone. Interactions involving higher multipoles that may be relevant in this case are not captured by classical fixed-charge force fields , potentially leading to the large deviations. Using QM calculations with QM-GNNIS, in contrast, reproduced the experimental trends much better (Fig. ), highlighting the benefits of QM-based methods for the description of more complex molecular interactions. : Comparison of predicted versus observed free-energy differences, ∆∆G, for the classical approach (OpenFF with GNNIS) and for QM calculations with QM-GNNIS for molecular balance A3. The experimental values were taken from Ref. , classical data from Ref. . The solid and dashed black lines indicate identity and deviations of half k b T, respectively. The color indicates the dielectric permittivity of the solvent (red: apolar, blue: polar).