hydrophilic in our model. Our main result -the large dependence of DDG Hyd,FEP on the identity of the amino acid and characteristics of the fluorinated site -is not affected by these force field shortcomings. Below we show that this dependence is in fact largely due to fluorination-induced conformational changes that alter the number of backbone-water hydrogen bonds. The AM-BER force field for proteins, upon which we build the force field for fluorinated amino acids, has been extensively improved for decades and is able to reproduce experimentally-measured structure and dynamics of folded small proteins . Fluorinationinduced changes in conformation in our simulations result from steric hindrance and favorable electrostatic carbonyl-CF interactions, both of which can be captured, at least qualitatively, by all-atom, fixed charge force fields. The surprising variation in DDG Hyd is largely Coulombic in origin. Decomposing the hydration free energy into Lennard-Jones and Coulombic contributions can be naturally done in sim-ulations, and gives valuable insight into the origin of the observed trends. The Lennard-Jones contribution to DDG Hyd (Figure ) is constant and positive per fluorinated group, positive but not constant for difluorinated amino acids and negative and constant for monofluorinated amino acids. Despite this variation in the LJ contribution to the free energy of hydration, the wide variation in DDG Hyd , particularly in the case of the partially fluorinated amino acids, is actually dominated by the Coulombic contribution to the free energy. This contribution varies seemingly unpredictably (Figure ), with each type of fluorination leading to either positive or negative DDG Coul Hyd : e.g., compare E2G with P2G, E1G with L1S, L1R and I1G, V3S with V3R. Previous reports on the dependence of lipophilicity on fluorine-induced polarity changes support the idea that the contribution of electrostatics to hydrophobicity is far from intuitive . Neither contribution shows visible correlation with local hydration around the fluorinated site, as measured by the radial distribution function of water around the fluorinated sites (SI section 5.2.4 and Figure ).