We used the TIP4P-Ew (ref. 31) water model, the AMBER14 (ff14sb; ref. 32) force field for the canonical amino acids and the GAFF force field for methane, ethane and propane. For the remaining amino acids and for the fluorinated small molecules, we used a force field developed by us (previous own work and SI sections 1 and 2) based on AMBER14 (amino acids) or GAFF (small molecules). The main difference between our force field for fluorinated molecules and GAFF/AMBER14 lies in the Lennard-Jones (LJ) parameters of fluorine, and of hydrogen (H F ) bonded to a fluorinated carbon. The LJ parameters of fluorine were optimized to reproduce the hydration free energies of CF 4 and the molar volume of a 50% mix of CF 4 and CH 4 ; subsequently, those of H F were optimized to reproduce the hydration free energy and the molar volume of CHF 3 . Atomic partial charges were obtained following the GAFF (small molecules) or AMBER (amino acids) protocols. We note that the requirement of compatibility with the protein force field implies that we retain the point charge representation. This representation has known shortcomings when modeling carbon-bound chlorine, bromine or iodine because these halogens exhibit s -holes (a positive area in the electrodensity distribution of the halogen atom, surrounded by a negative belt) which this charge model cannot represent . Carbon-bound fluorine, however, retains a negative potential in its entire surface and the level of anisotropy in its electronic charge distribution is small . For that reason, single point charge models have been used to model the interactions of fluorinated sites with water and with other organic molecules: e.g., Schyman & Jorgensen 34 , Ibrahim and Ho 39 apply their models of s -holes to carbon-bound chlorine, bromine and iodine, but retain a point charge representation for fluorinated sites. Point charge models perform less well in the case of fluorinated aryl groups because the s -hole perturbation extends into the b -carbons; when modeling fluorinated aryl molecules, other promising models such as those based on permanent atomic multipole charges should be considered. This extended perturbation occurs via the p electrons 37 , and consequently is not expected to be nearly as significant for fluorinated alkyl groups, which are the sole focus of the present work.