Simulated dynamic cholesterol redistribution favors membrane fusion pore constriction

Area of Science:

• Membrane biophysics
• Computational biology

Background:

• Membrane fusion pores form during endocytosis and exocytosis.
• Lipid composition influences fusion pore dynamics.
• Cholesterol's role in fusion pore geometry is debated due to competing effects of curvature and thickness.

Purpose of the Study:

• To investigate cholesterol redistribution in fusion pores.
• To determine whether curvature or thickness dictates cholesterol's location.
• To elucidate the role of cholesterol in fusion pore closure.

Main Methods:

• All-atom molecular dynamics simulations of specific fusion pore geometries.
• Theoretical modeling of lipid-bilayer mechanics.
• Comparison of simulation and theory to predict lipid behavior.

Main Results:

• Cholesterol is significantly excluded from the thinned neck regions of fusion and fission pores.
• Membrane thickness and lipid order, rather than negative curvature, are the primary drivers of cholesterol exclusion.
• Cholesterol exclusion creates a depleted zone that can promote fusion pore closure.

Conclusions:

• Cholesterol exclusion from thinned pore necks is a key mechanism influencing fusion pore dynamics.
• This finding supports models where cholesterol-dependent lateral phase separation drives membrane reshaping.
• Understanding lipid redistribution in fusion pores is crucial for cellular processes like vesicle trafficking.