Reference values for the thermodynamic quantities E sw , E ww , TS trans , TS orient and ∆G for each hydration site were obtained by averaging results from the MD simulation triplicates. In the case where MD simulations were compared to each other, average values were obtained by excluding the one compared. The predictions were compared by calculating the RMSD (in kcal/mol), as well as the coefficient of determination r 2 , Kendall τ , Spearman's ρ, (calculated using the corresponding Scipy functions 114 ). The energy evaluation was done using both all the hydration sites and the ligand binding site subset.