The amino acids with one or more -CH 3 ! -CF 3 substitutions (here termed fully fluorinated) are, as expected, always more hydrophobic than their non-fluorinated counterparts (positive DDG Hyd ) , but the change in free energy is not constant per fluorinated group. Even more surprisingly, amino acids with -CH 3 ! -CH 2 F/-CHF 2 and -CH 2 -! -CF 2 -substitutions (here termed partially fluorinated) display a range of DDG Hyd values from 1.5 kcal mol 1 to +1 kcal mol 1 , regardless of the number of fluorine atoms. DDG Hyd depends strongly and non-intuitively on the chirality (R/S), location (g vs. d ) of the fluorinated sites, and on the identity of the amino acid.