Multiscale Insights into the Ionic-Strength Dependence of α-Synuclein Liquid-Liquid Phase Separation

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Liquid-liquid phase separation (LLPS) of alpha-synuclein (α-syn) is a critical early event in pathogenic aggregation.
• The precise influence of sequence architecture and ionic strength on α-syn LLPS remains incompletely understood.

Purpose of the Study:

• To investigate how sequence features and ionic strength jointly regulate α-syn LLPS.
• To establish a mechanistic link between molecular dynamics, conformational ensembles, and condensate formation.

Main Methods:

• Utilized multiscale molecular dynamics (MD) simulations, including all-atom and coarse-grained approaches.
• Analyzed the phase-separation behavior of full-length α-syn and its distinct fragments (N-terminal, NAC, C-terminal) across varying NaCl concentrations.

Main Results:

• α-syn LLPS is highly sensitive to ionic strength; low to intermediate NaCl promotes liquid-like condensates with high internal mobility.
• Increased ionic strength attenuates and suppresses LLPS due to weakened electrostatic interactions via screening.
• The N-terminal region robustly phase separates through electrostatic interactions, unlike the NAC and C-terminal fragments.

Conclusions:

• Established a mechanistic link between salt-mediated electrostatic screening, region-specific conformational landscapes, and α-syn condensate formation.
• Demonstrated that solution conditions, particularly ionic strength, can modulate early aggregation events.