The electrostatic potential was calculated on a grid (0.1 Å of spacing) around the side chain of each amino acid, with conformations extracted from a 25 ns simulation of each amino acid in water, using only the partial charges of the side chain atoms. Then, the electrostatic potential was interpolated to the coordinates of oxygen atoms belonging to water molecules within a radius of 5.5 Å of the side chain carbon atoms; this radius corresponds to the first minimum of the radial distribution function of water oxygen atoms near methane's carbon atom, that is, it corresponds to the farther limit of the first hydration shell of methane. The probability density distributions of the electrostatic potential, F, at these positions is shown in SI Figure B-F. For each fluorinated amino acid, the DF + term in Equation 1 in the main text corresponds to the number of water molecules, within 5.5 Å of the side chain carbon atoms, that experience a potential which is more positive than that of the waters at the 90 th percentile of the F probability distribution of the corresponding non-fluorinated amino acid. SI Figure shows the electrostatic potential F around the side chain of ETG, E1G, E2G and E3G.