Developing an analytical solvation model to understand how fluorination affects DG Hyd . Can we understand the origin of these hydration free energies? To answer this question we model the fluorination-induced change in hydration free energy in terms of linear, multivariate models of the form DDG Hyd = Â i k i • DY i , where k i are fitting parameters and Y i are observables that should affect the hydration free energy and can be easily calculated in short molecular dynamics simulations. The LJ contribution to DDG Hyd is dominated by the energy (work) required to form a solute-sized cavity in water to accommodate the larger fluorine atoms. This contribution (Table ) is proportional to the change in solvent accessible surface area (DSASA) of the amino acid , and can be easily quantified by measuring DSASA in molecular dynamics simulations, and multiplying it by the LJ component of DG Hyd per surface area unit of methane, which is essentially identical to that of CF 4 (SI Table ).