Postsynaptic protein assembly in three and two dimensions studied by mesoscopic simulations.

Area of Science:

• Cellular biology
• Biophysics
• Neuroscience

Background:

• Cellular biomolecular condensates form via phase separation in 3D (cytosol) or 2D (beneath membranes).
• Postsynaptic density (PSD) is a membrane-associated protein condensate crucial for synaptic plasticity.
• Previous studies show liquid-liquid phase separation of soluble PSD proteins, but 2D behavior is unclear.

Purpose of the Study:

• To compare phase separation behaviors of protein assemblies in 3D and 2D systems.
• To investigate how membrane-bound proteins form condensates and affect receptor localization.
• To model protein-domain interactions in PSD using AMPAR-TARP and PSD-95.

Main Methods:

• Developed a mesoscopic model of protein-domain interactions in PSD.
• Performed comparative molecular simulations for 3D and 2D systems.
• Focused on the mixture of AMPAR-TARP complex and PSD-95.

Main Results:

• 3D simulations showed phase-separated condensates of soluble AMPAR-TARP and PSD-95, consistent with experiments.
• 2D simulations with identical interactions revealed AMPAR-TARP/PSD-95 clustering but no stable phase separation.
• Protein assembly behaviors differed significantly between 3D and 2D environments.

Conclusions:

• Stable phase separation is more challenging in 2D (membrane-associated) systems compared to 3D systems.
• Distinct cluster formation behaviors in 3D and 2D impact protein localization at synapses.
• Findings provide general insights into biomolecular condensate formation at cellular interfaces.