The correlation between the energy required to form an amino acid-sized cavity in water and the energy gain from the formation of water-fluorine hydrogen bonds is found in SI Figure . It is clear that both the penalty associated with the surface area and the gain from hydrogen bond formation decrease with the increasing number of fluorine atoms per fluoromethyl group. The term k B T ln[g(r)] corresponds to the PMF, with k B being the Boltzmann constant, T the system temperature and g(r) the radial distribution function. The term g(r)V (r) r Bulk is the particle density of water in a volume V(r) corresponding to the difference in volume of two spheres, one with radius r and the other with radius r 0.02 (the spacing between values of r at which the g(r) is calculated); r Bulk is the particle density of bulk TIP4P-Ew water. The summation in Equation runs over values of r between r 0 (the C-O distance at which g(r) > 0) and r Shell (the radius of the hydration shell of either methane, 5.531Å, or tetrafluoromethane, 5.690Å). Defining r shell as the value for which each g(r) reached its first minimum did not alter the trends described below.