The preferential interaction between apolar solutes in waterthe hydrophobic effect -is a key factor driving protein folding , structural stability with respect to changes in temperature (thermal stability) and interactions with other proteins and ligands . The hydrophobic effect reflects the balance between solute-water interactions and direct, predominantly dispersive, solute-solute interactions . Understanding how to use amino acid mutations to control the hydrophobic effect is critical to develop new protein-based drugs, biodevices and materials . Simultaneously, minimizing changes in solute-solute packing upon mutations is desirable to ensure that protein structure -and thus function -is preserved . This is, however, difficult with the limited pool of canonical hydrophobic amino acids because their side chains differ in structure and volume. Fluorinated versions of those amino acids, i.e. those where hydrogen atoms in side chain groups are substituted by fluorine (see Figure ), can solve this problem while simultaneously enhancing other properties of interest . Even fluorinating only a few residues may enhance the hydrophobicity and passive diffusion of peptides through membranes 20 , the proteolytic resistance and anti-microbial activity of proteins , in addition to tuning their thermal stability , making this synthetic approach of wide interest .