Experimental hydration free energies for amino acids are not available, so we cannot directly assess the accuracy of our predictions. To test the accuracy of our force field, we applied it to all fluorinated variants of methane, ethane and propane for which experimental hydration free energies could be found . These small molecules are the closest analogues to the side chains of the amino acids investigated here. The free energies of hydration for the fluorinated small molecules are shown in Figure and SI Table . We show also the free energies of hydration of methane, ethane and propane, to illustrate the accuracy of the AMBER force field for the alkyl side chains of amino acids. The force field for fluorinated molecules reproduces the experimental hydration free energy very well in most cases. The largest deviation is seen for CH 3 F, whose DG Hyd is 0.8 kcal mol 1 too negative. The predicted hydration free energies for methane, ethane and propane, in contrast, are too positive by 0.5 to 0.8 kcal mol 1 . These results suggest that the predicted DDG Hyd for amino acids (Figure ) may be systematically too negative by 0.5 to 0.8 kcal mol 1 . Differences between di-and trifluorinated amino acids should be well captured, but monofluorinated alkyl groups are likely excessively for free energy values.