RDFs of water around the fluorinated site do not give insight into local contributions to the DG Hyd . Given that the impact of fluorination on local solvation is fairly constant for groups with the same number of fluorine atoms (Figure ), we investigated whether these local changes in solvation correlate well with the radial distribution function (RDF) of water around methyl or fluoromethyl groups. Specifically, we calculated the excess free energy, DDG Shell,PMF , necessary to populate the first hydration layer of methyl or fluoromethyl groups from the potential of mean force associated with each radial distribution function. Our results (SI section 5.2.4, Figure ) show that such a correlation is at best very weak. We could also not find correlations between DDG Shell,PMF and the Coulomb and Lennard-Jones components of the hydration free energy (SI Figure ). Radial distribution functions describe solvation along a single reaction coordinate, which may be insufficient to give quantitative or semi-quantitative insight into local hydrophobicity. In contrast, proximal radial distribution functions -i.e., those calculated perpendicular to the solute atoms -appear near universal for proteins and have proven useful to estimate hydration free energies of small molecules and peptides . Exploring their usefulness for fluorinated molecules is outside the scope of the present work.