Effects of single substitutions with hexafluoroleucine and trifluorovaline on the hydrophobic core formation of a heterodimeric coiled coil

Structural modifications of peptides and proteins using fluorinated amino acids provide the opportunity to modulate their biophysical and pharmaceutical properties. Systematic investigations based on model systems that mimic natural protein-protein interaction domains, such as the coiled-coil folding motif, can provide valuable insights into the behaviour of side chain fluorinated amino acids in natural protein environments. Here, we report the incorporation of hexafluoroleucine and two trifluorovaline stereoisomers at two different hydrophobic core positions of an established parallel heterodimeric coiled-coil model system to evaluate the impact of these substitutions on coiled-coil structure and stability. All of the resulting fluorinated peptides form stable α-helical bundles, and the single substitution of leucine with hexafluoroleucine leads to an increase in thermal stability.