The complete free-energy profiles of compound I1 in a selection of four low dielectric solvents (i.e., dielectric permittivity < 10) and four high dielectric solvents (i.e., dielectric permittivity > 30) are depicted in Figure and D, respectively. As expected, the profiles in the individual solvents diverge significantly despite their similar dielectric permittivities, which can be reproduced by the GNNIS model. In contrast, simulations with the state-of-the-art implicit solvent model GB-Neck2 show significant deviations from the explicit-solvent reference. The median absolute error with GB-Neck2 is 2.5 kJ mol -1 compared to 0.6 kJ mol -1 for GNNIS (SI Figures ). Notably, this is achieved with the GNNIS model at a significantly reduced computational cost. While the explicit-solvent simulations can only simulate one system at a time, the GNNIS model runs multiple systems in parallel, achieving a speed-up of 10 fold (1750 ns d -1 versus 16 900 ns d -1 on the same hardware (8 CPU cores + 1 NVIDIA RTX 4090 GPU).