Cholesterol Promotes Protein Binding by Affecting Membrane Electrostatics and Solvation Properties

Area of Science:

• Structural biology
• Biophysics
• Virology

Background:

• Retroviral structural protein Gag binds to the plasma membrane via its matrix (MA) domain.
• MA-membrane interactions are primarily electrostatic, involving attraction between the positively charged MA and the negatively charged inner leaflet.
• Previous studies showed membrane association depends on acidic lipids and is enhanced by cholesterol (Chol), but the mechanism was unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms of Rous sarcoma virus (RSV) MA association with model membranes.
• To investigate how cholesterol enhances this MA-membrane association.

Main Methods:

• In vitro and in silico techniques were employed.
• Neutron scattering experiments with liposomes.
• Molecular dynamics simulations.
• Continuum electrostatic theory.

Main Results:

• MA preferentially binds to preexisting POPS-rich clusters with minimal bilayer perturbation.
• Cholesterol enhances MA-bilayer interaction, increases lipid packing, and elevates membrane surface charge density.
• MA-liposome association depends on membrane surface potential, influenced by ionic strength, cholesterol, and charged lipids.

Conclusions:

• Cholesterol enhances RSV MA-membrane association by increasing negative membrane surface potential and reducing lipid headgroup desolvation penalty.
• The findings provide a mechanistic understanding of cholesterol's role in viral protein-membrane interactions.
• The presented approach is applicable to other protein-membrane systems.