Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine

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

Research output: Contribution to journal › Article

160 Citations (Scopus)

Abstract

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
JournalBiochemistry
Volume40
Issue number9
DOIs
Publication statusPublished - Mar 6 2001

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Stabilization
Peptides
Fluorination
Hot Temperature
Halogenation
Thermodynamic stability
Leucine Zippers
Proteins
Protein Stability
DNA sequences
Solvation
Molecular Dynamics Simulation
Protein Domains
Binding energy
Leucine
Free energy
Molecular dynamics
Substitution reactions
Ligands
Temperature

ASJC Scopus subject areas

  • Biochemistry

Cite this

Tang, Y., Ghirlanda, G., Vaidehi, N., Kua, J., Mainz, D. T., Goddard, W. A., ... Tirrell, D. A. (2001). Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. Biochemistry, 40(9), 2790-2796. https://doi.org/10.1021/bi0022588

Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. / Tang, Y.; Ghirlanda, Giovanna; Vaidehi, N.; Kua, J.; Mainz, D. T.; Goddard, W. A.; DeGrado, W. F.; Tirrell, D. A.

In: Biochemistry, Vol. 40, No. 9, 06.03.2001, p. 2790-2796.

Research output: Contribution to journal › Article

Tang, Y, Ghirlanda, G, Vaidehi, N, Kua, J, Mainz, DT, Goddard, WA, DeGrado, WF & Tirrell, DA 2001, 'Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine', Biochemistry, vol. 40, no. 9, pp. 2790-2796. https://doi.org/10.1021/bi0022588
Tang Y, Ghirlanda G, Vaidehi N, Kua J, Mainz DT, Goddard WA et al. Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. Biochemistry. 2001 Mar 6;40(9):2790-2796. https://doi.org/10.1021/bi0022588
Tang, Y. ; Ghirlanda, Giovanna ; Vaidehi, N. ; Kua, J. ; Mainz, D. T. ; Goddard, W. A. ; DeGrado, W. F. ; Tirrell, D. A. / Stabilization of coiled-coil peptide domains by introduction of trifluoroleucine. In: Biochemistry. 2001 ; Vol. 40, No. 9. pp. 2790-2796.
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AB - 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.

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