Modulation of α-synuclein aggregation amid diverse environmental perturbation

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Intrinsically disordered protein alpha-synuclein (αS) aggregation is central to Parkinson's disease pathogenesis.
• Understanding αS aggregation mechanisms is crucial for developing therapeutic strategies.

Purpose of the Study:

• To computationally simulate the multi-chain association of αS under various environmental conditions.
• To elucidate the factors governing αS aggregation and liquid-liquid phase separation (LLPS).

Main Methods:

• Multi-chain association simulations of αS.
• Analysis of protein aggregate concentration, surface tension, and conformational changes.
• Graph theory analysis to identify interaction networks within αS droplets.

Main Results:

• αS aggregation in aqueous and perturbed environments promotes liquid-liquid phase separation (LLPS).
• Saline and crowded conditions enhance LLPS propensity, with distinct surface tension responses.
• αS chains adopt extended conformations with perpendicular orientations to minimize repulsion, stabilized by C-terminal interactions.

Conclusions:

• Environmental factors significantly modulate αS aggregation and LLPS behavior.
• αS droplets exhibit small-world network characteristics, indicating conserved interaction patterns.
• A balance between intrinsic protein properties and environmental cues dictates αS aggregation dynamics.