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Modulation of Coiled-Coil Binding Strength and Fusogenicity through Peptide Stapling
Niek S A Crone1, Alexander Kros1, Aimee L Boyle1
1Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Bioconjugate Chemistry
|February 15, 2020
Summary
Peptide stapling constrains peptide structure, altering binding interactions. This study demonstrates how stapled peptides can enhance fusogenicity in liposome systems by modulating binding entropy and enthalpy.
Area of Science:
- Biochemistry
- Biophysics
- Molecular Biology
Background:
- Peptide conformation influences molecular interactions.
- Peptide stapling is a method to stabilize peptide structures.
- Constrained peptides can exhibit altered binding affinities and functions.
Purpose of the Study:
- To investigate the impact of peptide stapling on the structure, stability, and binding thermodynamics of a heterodimeric coiled-coil peptide.
- To evaluate the effect of different macrocycle positions and sizes on peptide properties.
- To assess the fusogenic capabilities of stapled peptides in a liposome model system.
Main Methods:
- Cysteine bis-alkylation stapling technique to create structurally isomeric peptide variants.
- Isothermal titration calorimetry (ITC) for analyzing binding thermodynamics (entropy and enthalpy).
- Liposome-based assays to measure lipid and content mixing for fusogenicity.
Main Results:
- C-terminal stapling significantly altered peptide structure and stability.
- Stapled variants exhibited reduced binding entropy, dependent on cross-linker size, with associated changes in binding enthalpy.
- One stapled peptide variant demonstrated increased fusogenicity, indicated by enhanced lipid and content mixing in liposomes.
Conclusions:
- Peptide stapling effectively modulates binding entropy and enthalpy, providing insights into preorganization effects.
- The enhanced fusogenicity of a stapled peptide variant is linked to increased coiled-coil binding, not membrane affinity.
- Peptide stapling offers a strategy to engineer peptide function for applications like membrane fusion.
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