The polar contribution is dominated by the interaction of a distribution of atom-centered point charges with water. This contribution can be estimated in multiple manners . We first attempted to model the polar contribution as the sum of three terms, one proportional to a global quantity, the dipole moment µ, representing the molecular charge distribution, and the other two proportional to local quantities, the number of hydrogen bonds between water and amines (h NH ) or carbonyls (h CO ) in the backbone ⇤ . Fitting the DDG Hyd values calculated with FEP using a linear multivariate model (SI Equation ) consisting of the sum of the contributions arising from changes in SASA, µ, h NH , and h CO due to fluorination was unsuccessful: the resulting fitting parameters had unphysical values, e.g., a positive energetic contribution of the dipole moment, and overly large errors (SI Table ). We also attempted to model our data using an analogous version of this model, but where the area term reflects the difference in hydration free energy between CH 4 and CF 4 . This second model (SI Equation ) has proven successful to understand hydrophobicity of tri-and hexa-fluorinated amino acids 33 , but it fails (SI Figure ) when applied to the partially fluorinated amino acids. Given that the contributions of solute-water hydrogen bonds and the Lennard-Jones interactions to the hydration free energies are well-known 33,66,68 , we interpret these results as an inability of the molecular dipole moment to describe electrostatic solute-water interactions in a quantitative manner, at least for solutes as diverse as the current set of amino acids. We next attempted to characterize how fluorination alters the solute-water electrostatic interactions with another commonly used global descriptor: solving the linearized Poisson-Boltzmann (PB) equation, where the solvent is modeled as a continuum, as described in SI Section 3.1. Given the apparently simple problem we were trying to model, we were surprised to find that the electrostatic component of the hydration free energy calculated using PB hardly correlates with the reference FEP values (SI Figure ). The ab-