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Updated: Jun 16, 2026
Using Scaffold Liposomes to Reconstitute Lipid-proximal Protein-protein Interactions In Vitro
Published on: January 11, 2017
Variation of the lateral mobility of transmembrane peptides with hydrophobic mismatch
Yann Gambin1, Myriam Reffay, Emma Sierecki
1Laboratoire de Physique Statistique, Ecole Normale Supérieure, Université Paris Diderot, CNRS, 24 rue Lhomond, 75005 Paris, France.
Abstract:
A hydrophobic mismatch between protein length and membrane thickness can lead to a modification of protein conformation, function, and oligomerization. To study the role of hydrophobic mismatch, we have measured the change in mobility of transmembrane peptides possessing a hydrophobic helix of various length d(pi) in lipid membranes of giant vesicles. We also used a model system where the hydrophobic thickness of the bilayers, h, can be tuned at will. We precisely measured the diffusion coefficient of the embedded peptides and gained access to the apparent size of diffusing objects. For bilayers thinner than d(pi), the diffusion coefficient decreases, and the derived characteristic sizes are larger than the peptide radii. Previous studies suggest that peptides accommodate by tilting. This scenario was confirmed by ATR-FTIR spectroscopy. As the membrane thickness increases, the value of the diffusion coefficient increases to reach a maximum at h approximately = d(pi). We show that this variation in diffusion coefficient is consistent with a decrease in peptide tilt. To do so, we have derived a relation between the diffusion coefficient and the tilt angle, and we used this relation to derive the peptide tilt from our diffusion measurements. As the membrane thickness increases, the peptides raise (i.e., their tilt is reduced) and reach an upright position and a maximal mobility for h approximately = d(pi). Using accessibility measurements, we show that when the membrane becomes too thick, the peptide polar heads sink into the interfacial region. Surprisingly, this "pinching" behavior does not hinder the lateral diffusion of the transmembrane peptides. Ultimately, a break in the peptide transmembrane anchorage is observed and is revealed by a "jump" in the D values.
Insights
Hydrophobic mismatch between transmembrane peptides and lipid membranes alters peptide behavior. Optimal mobility and upright conformation occur when membrane thickness matches peptide length, while excessive thickness causes "pinching" without hindering diffusion.
Area of Science:
- Biophysics
- Membrane Biology
- Protein-Lipid Interactions
Background:
- Hydrophobic mismatch between proteins and lipid bilayers affects protein conformation and function.
- Transmembrane peptides are crucial for various cellular processes.
Purpose of the Study:
- To investigate the impact of hydrophobic mismatch on transmembrane peptide mobility and conformation.
- To quantify peptide behavior across varying lipid bilayer thicknesses.
Main Methods:
- Utilized giant vesicles and a tunable model system to control lipid bilayer hydrophobic thickness (h).
- Measured peptide diffusion coefficients and apparent sizes using precise diffusion measurements.
- Employed Attenuated Total Reflection Fourier-Transform Infrared (ATR-FTIR) spectroscopy to confirm peptide tilting.
- Conducted accessibility measurements to assess peptide interactions with interfacial regions.
Main Results:
- Decreased diffusion coefficients and increased apparent sizes were observed for bilayers thinner than the peptide hydrophobic length (d(pi)), indicating peptide tilting.
- Diffusion coefficients increased with membrane thickness, reaching a maximum when h approximated = d(pi), correlating with reduced peptide tilt.
- Transmembrane peptides adopted an upright position and maximal mobility at optimal membrane thickness.
- Despite a "pinching" effect in thicker membranes, lateral diffusion remained unaffected until a critical point where transmembrane anchorage broke.
Conclusions:
- Peptide tilt and mobility are significantly influenced by the hydrophobic mismatch with the surrounding lipid bilayer.
- The optimal membrane thickness for transmembrane peptide function and mobility is approximately equal to the peptide's hydrophobic length.
- The study provides a quantitative relationship between diffusion coefficient and peptide tilt angle, offering insights into membrane protein dynamics.
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