135 and 180 sence of correlation suggests that it is imperative to model the solvent as discrete water molecules. Thus, when aiming for a correct characterization of how aqueous solvation of biopolymers changes with mutations, not only the solute but also the solvent must be modeled without the use of global or mean-field descriptors. Backbone-water hydrogen bonds dominate the polar interactions between the backbone and water ; the unresolved issue is how to describe polar interactions between the side chain and water. We find that these can be characterized by the electrostatic potential, F, at the position of the water oxygen atoms in the hydration shell of the side chains, as described in SI Section 4. The corresponding probability distributions of F for the fluorinated amino acids, shown in SI Figure B-F, show large negative potential regions together with, in some cases, regions of more positive potentials than observed for the parent amino acid. The more positive potential, almost exclusive to mono-and difluorinated species, arises from a larger exposure of the positively charged carbon skeleton of the side chain, left partially unshielded by hydrogen in mono-and difluorinated groups (see SI Section 4 and SI Figure ). The negative potential region, observed for all amino acids, can be attributed to the fluorine atoms. Water molecules near fluorine atoms often assume configurations that meet the geometric criteria for HOH•••FC hydrogen bonds, as discussed in SI section 5.2, so we consider that these weak hydrogen bonds exist. This interpretation is consistent with ab initio calculations, and spectroscopic measurements ; the strong correlation between F NMR isotropic chemical shifts and the type of fluorineprotein interactions observed in the Protein Data Bank also suggest that hydrogen bonds to fluorinated alkyl groups exist, and are strongest for groups with low degrees of fluorination , as we also observe (SI Table ).