predicted large free energy differences correlate with the lack in convergence of the estimates (second row, fourth column). While there are many factors influencing convergence of an alchemical perturbation, we observed that a simple count of heavy atoms that need to be introduced/annihilated correlates slightly with the absolute error (third row, last column) and well with the convergence measure (fourth row, last column). Similar trends can be seen All in all, this simple trace through the dependencies in the data already reveals some of the determinants limiting the accuracy of our predictions. For larger perturbations, the calculation convergence suffers, thus reducing the agreement between the prediction and experiment. It is important to note, however, that the identified signal is noisy, i.e. not every large perturbation will be inaccurate and not all well converged simulations will yield perfect binding free energy prediction. The identified determinants for prediction accuracy are only general trends in a complex picture. and their effect on the predicted free energy accuracy for the cases where the effect is statistically significant. For example, an ester group has an angle (OpenFF code a15), bond (b20), improper (i2), and torsion (t107, t110) changes. Altogether, the RMSE between the predicted and experimental ∆∆G for the perturbations of ester groups drops by 0.5 kcal mol -1 .