Cholesterol modulates the structure, binding modes, and energetics of caveolin-membrane interactions

Area of Science:

• Molecular biology
• Biophysics
• Computational chemistry

Background:

• Caveolin-1 (cav-1) is a key membrane protein involved in cellular signaling and trafficking.
• Cav-1 organizes membrane domains and interacts with cholesterol-rich environments to form structures like caveolae.

Purpose of the Study:

• To investigate the molecular interactions between caveolin-1 peptides and various model lipid bilayers using simulations.
• To understand how cholesterol content affects cav-1 binding, orientation, and membrane morphology.

Main Methods:

• Coarse-grain molecular dynamics simulations were employed.
• Interaction of cav-1 peptides with cholesterol-rich, cholesterol-depleted, and unsaturated lipid bilayers was studied.
• Partitioning free energy calculations were performed.

Main Results:

• Cholesterol modulates the binding depth and orientation of cav-1 peptides.
• Cholesterol stabilizes more open cav-1 conformations, potentially driving membrane morphological changes.
• Binding is most favorable to cholesterol-rich bilayers, less favorable to cholesterol-depleted, and least favorable to unsaturated bilayers.
• Cav-1 binding alters bilayer pressure profiles and local spontaneous curvature in cholesterol-rich membranes.

Conclusions:

• The study provides molecular-level insights into the interplay between caveolin-1 and lipids.
• Findings suggest cav-1's role in tuning the morphology of cholesterol-rich membranes.
• The observed binding modes and conformations offer explanations for cav-1's effect on membrane structure.