Still, a caveat of using fluorination to control protein properties remains: do we understand the factors influencing the hydropho-Max Planck Institute for Colloids and Interfaces, Department of Theory & Bio-systems, Science Park, Potsdam 14424 Germany. Fax: +49 (0)331 5679602; Tel: +49 (0)331 5679608; E-mail: ana.vilaverde@mpikg.mpg.de † Electronic Supplementary Information (ESI) available: Description of force fields and simulation details, hydration free energies, electrostatic potential in the vicinity of amino acid side chains, linear models to reproduce the calculated hydration free energies, radial distribution functions, conformational changes in fluorinated side chains. AMBER-format force fields for mono-and di-fluorinated amino acids available upon request. bic effect involving fluorinated amino acids? The answer is, simply, that we do not. Here we focus on one factor contributing to the hydrophobic effect: solute-water interactions, for simplicity referred to as solute hydrophobicity. The hydrophobicity of solutes is usually characterized by their hydration free energies . The hydrophobicity of fluorinated amino acids has been qualitatively estimated by considering the surface area of its side chain (the larger the surface area, the larger the hydrophobicity) and its side chain polarity (the larger the polarity, the smaller the hydrophobicity) , but detailed mechanistic understanding is still lacking . Understanding the origins of fluorinationinduced changes in hydrophobicity depends critically on our ability to accurately quantify interactions between amino acids and their environment. We demonstrate that this quantification is now possible using molecular dynamics simulations and fixedcharge, all-atom models. The approach presented here is general, and may be used to investigate the hydrophobicity of any fluorinated (bio)polymer or small molecule.