The model captures the difference in hydration free energies between the partially fluorinated amino acids and their non-fluorinated counterparts less well than for the fully fluorinated ones (Figure in the main text). The cause for this discrepancy could possibly be related to an inadequacy of a linear model to represent either or both the water-fluorine hydrogen bond and the electrostatic potential terms in Equation 1 in the main text. To test the validity of using Equation (see main text) to calculate the hydration free energy differences between fluorinated and non-fluorinated amino acids, we have calculated P-values for the DDG Hyd of each amino acid by excluding it from the fit to Equation in the main text. These P-values are presented in SI Table and show that, particularly for E1G, E2G, I3D, L1S, L4D and L3S, the hydration free energy differences calculated with this type of model are not representative of those calculated with FEP. Using all amino acids to perform the fit, the P-values show an improvement (SI Table ), where only E2G, L1S, L4D and L3S are not representative at a confidence level of 99%. Apart from E1G, E2G, I3D, L1S, L4D and L3S, all DDG Hyd values are representative to a confidence level of 90%. The emphasis should then be placed at the qualitative description of the observed trends in DDG Hyd , observed in Figure of the main text, which is the central message of this work.