Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine

Y. Tang, G. Ghirlanda, N. Vaidehi, J. Kua, D. T. Mainz, W. A. Goddard, W. F. DeGrado, D. A. Tirrell

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164 Citations (Scopus)


Substitution of leucine residues by 5,5,5-trifluoroleucine at the d-positions of the leucine zipper peptide GCN4-p1d increases the thermal stability of the coiled-coil structure. The midpoint thermal unfolding temperature of the fluorinated peptide is elevated by 13°C at 30 μM peptide concentration. 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/mol larger than that of the hydrogenated form. A similarly fluorinated form of the DNA-binding peptide GCN4-bZip binds to target DNA sequences with affinity and specificity identical to those of the hydrogenated form, while demonstrating enhanced thermal stability. Molecular dynamics simulation on the fluorinated GCN4-p1d peptide using the Surface Generalized Born implicit solvation model revealed that the coiled-coil binding energy is 55% more favorable upon fluorination. These results suggest that fluorination of hydrophobic substructures in peptides and proteins may provide new means of increasing protein stability, enhancing protein assembly, and strengthening receptor - ligand interactions.

Original languageEnglish
Pages (from-to)2790-2796
Number of pages7
Issue number9
Publication statusPublished - Mar 6 2001

ASJC Scopus subject areas

  • Biochemistry

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    Tang, Y., Ghirlanda, G., Vaidehi, N., Kua, J., Mainz, D. T., Goddard, W. A., DeGrado, W. F., & Tirrell, D. A. (2001). Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. Biochemistry, 40(9), 2790-2796.