For all the QM/MM and ML/MM simulations, 5 ps of sampling per window was obtained and integrated using WHAM. Such a short sampling time was chosen to limit the computational resources required for the reference 2D FES at the ωB97X/6-31G* level of theory. This functional was chosen for a fair comparison with the ANI-2x potential which used the same functional as the reference in training. All QM calculations were performed using ORCA 5.0.3. To estimate the statistical error of the resulting PMF, we performed 2D US at the MM level using 1 ns sampling per window, and the PMF was calculated both using the complete data set (1 ns per window) and by splitting the windows into two hundred 5 ps chunks. The mean error of the bins from the resulting 200 PMFs with 5 ps sampling per window compared to the full PMF was 0.3 kcal•mol -1 , which is below the error of the most precise of the tested ML/MM potentials (see below) and therefore justifies the usage of just 5 ps per window for the DFT reference and ML/MM models.