Substitution of leucine residues by 5,5,5-trifluoroleucine at the d-positio
ns of the leucine zipper peptide GCN4-pld increases the thermal stability o
f the coiled-coil structure. The midpoint thermal unfolding temperature of
the fluorinated peptide is elevated by 13 degreesC at 30 muM peptide concen
tration. The modified peptide is more resistant to chaotropic denaturants,
and the free energy of folding of the fluorinated peptide is 0.5-1.2 kcal/m
ol larger than that of the hydrogenated form. A similarly fluorinated form
of the DNA-binding peptide GCN4-bZip binds to target DNA sequences with aff
inity and specificity identical to those of the hydrogenated form, while de
monstrating enhanced thermal stability. Molecular dynamics simulation on th
e fluorinated GCN4-pld peptide using the Surface Generalized Born implicit
solvation model revealed that the coiled-coil binding energy is 55% more fa
vorable upon fluorination. These results suggest that fluorination of hydro
phobic substructures in peptides and proteins may provide new means of incr
easing protein stability, enhancing protein assembly, and strengthening rec
eptor-ligand interactions.