Conveniently, the low predictive power for E ww results in a low error amplitude (0.52 kcal/mol), due to the relatively small energy range of this term, and in agreement with what observed also in the reference MD simulations. As a consequence, errors in this term will have only limited impact on the accuracy final ∆G predictions. Conversely, since E sw is the dominating thermodynamic term, one might argue that this term alone could be used to calculate a sufficiently accurate estimate of the hydration sites E sw . To test this hypothesis, MD-derived hydration sites were used to calculate E sw energies by interpolating the TIP3P model and AutoDock Vina spherical maps, then values were compared to those obtained with MD trajectories. Results yield little to no correlation between them (Table ), showing that using a crude single-point probe without proper sampling is insufficient to reproduce the full spectrum of thermodynamic properties obtained by processing the results of multi-state simulations.