Decomposing the contributions to DDG Hyd . The performance of the multivariate model is sufficiently good to enable insight into the mechanisms of fluorination-induced changes in solvation, by decomposing the individual contributions to DDG Hyd as seen in Figure . Surface area. Within derivatives of the same amino acid, the surface area increases DDG Hyd proportionally to the number of fluorine atoms (SI Figure ). The magnitude of the increase per fluorine atom depends on the amino acid identity, which implies that the hydration shells around each side chain are disturbed to a different degree, when accommodating the hydrogen ! fluorine substitution -compare, e.g. E2G with P2G. Backbone-water hydrogen bonds. The contribution of hydrogen bonds between water and carbonyl groups is always positive because fluorination reduces the number of these hydrogen bonds by steric blockage. The magnitude of this contribution, for fluorinated variants of a given amino acid, is again proportional to the number of fluorine atoms in the side chain. In contrast, the contribution of amine-water hydrogen bonds varies between positive and negative because fluorination may increase or decrease the number of these hydrogen bonds. Steric blockage occurs because of fluorine's large size and, for some amino acids, because fluorination changes the preferential conformation of the side chain as discussed in SI section 6. These results are consistent with previous reports indicating that CF and carbonyl groups interact favorably , and that changes in the conformational preference of fluorinated alkyl groups affect a molecule's lipophilicity, membrane permeability and inhibitory activity .