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

Liquid-liquid phase separation (LLPS) of α-synuclein (α-syn) is an early step toward pathogenic aggregation, yet how sequence architecture and ionic strength jointly regulate this process remains unresolved. Here, we combine all-atom and coarse-grained molecular dynamics simulations to connect single-chain conformational ensembles with multichain condensate formation of α-syn. The highly disordered nature of the α-syn monomer is consistently captured by both all-atom simulations and coarse-grained simulations. We find that the LLPS behavior of full-length α-syn is strongly dependent on ionic strength. Low to intermediate NaCl concentrations favor the formation of liquid-like condensates characterized by high internal mobility and continuous exchange with the dilute phase. As ionic strength increases, electrostatic screening weakens intermolecular interactions, and LLPS is progressively attenuated and ultimately suppressed. We next examined the phase-separation propensities of the N-terminal, NAC, and C-terminal fragments. Strikingly, robust phase separation is observed only for the N-terminal region due to electrostatic interactions, whereas the NAC and C-terminal fragments exhibited only weak, short-lived clustering without forming persistent condensates. Together, our multiscale results establish a mechanistic link between salt-mediated electrostatic screening, region-encoded conformational landscapes, and α-syn condensate formation, providing molecular insight into how solution conditions may tune early events along the pathway to aggregation.