Figure shows the correlation between the FEP-calculated hydration free energies and the ones calculated using Equation . The model describes the changes in DG Hyd following fluorination for most cases, with an average deviation between model and FEP results of only 0.26 kcal mol 1 . Poorer agreement occurs for E1G, for which it yields a value of DDG Hyd which deviates 0.5 kcal mol 1 from the value given by the FEP simulations and actually has the wrong sign, and for E2G, L4D and L3S, for which deviations are 0.7, 0.5 and 0.5 kcal mol 1 each. Our prior work suggests that the source of these large deviations might be entropic , and we speculate it might be related to changes in solute conformational entropy, which are not included in Equation 1. Clarifying this point is outside of the scope of the present work.