Phase separation in alpha-synuclein solution through micro-structural organization

alpha-synuclein has the characteristics of an intrinsically disordered protein due to highly concentrated charges at the termini and a low overall hydrophobicity. It can misfold and aggregate into highly structured and beta-sheet containing amyloid fibrils, the hallmarks of Parkinson's disease (PD). Involvement in the pathogenesis of PD has led to significant experimental and theoretical efforts to understand its aggregation mechanism. Although a few studies suggest droplet formation and a subsequent phase transition to amyloid fibrils, the exact phase behavior is not well understood. To shed light onto the structural organization of alpha-synuclein aggregates, we investigate the phase behavior using multi-scale numerical simulations. We observe that micro-structural organization emerges in the solution beyond a threshold protein concentration. This organization of the protein chains is mainly driven by the electrostatic interactions between the residues in N-terminal and C-terminal of the proteins. Moreover, the presence of salt ions loosens up the compactness of the micro-structure, which can be a promising pathway to hinder aggregation into droplets and ultimately amyloid formation.