Membrane-binding mechanism of a peripheral membrane protein through microsecond molecular dynamics simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Oxysterol binding proteins (Oshs) are essential for lipid transport and membrane contact.
• Osh4, a homologue in yeast, peripherally binds to membranes, facilitating lipid transfer.

Purpose of the Study:

• To characterize the structure and mechanism of Osh4's attachment to model lipid membranes.
• To elucidate the role of specific lipid compositions and protein domains in Osh4-membrane interactions.

Main Methods:

• Extensive molecular dynamics simulations of Osh4 interacting with various model lipid membranes.
• Analysis of protein conformation, binding sites, and interaction dynamics.

Main Results:

• Osh4 exhibits a single binding conformation on anionic membranes (high PS/PI(4,5)P2 or low PI(4,5)P2), involving loops and the lipid-binding pocket mouth.
• Binding is weak and transient on zwitterionic membranes.
• The β14-β15 loop shows strong, non-specific interaction with anionic lipids.
• A phenylalanine loop (aa 236-244) acts as an anchor, stabilizing interactions critical for lipid binding/release.

Conclusions:

• Osh4 utilizes a single, adaptable binding conformation on anionic membranes, distinct from previous models.
• The phenylalanine loop anchor is critical for stabilizing Osh4-membrane interactions and facilitating lipid transport.
• These findings provide a detailed mechanistic understanding of Osh4's role in membrane lipid dynamics.