Modulators selectively reshape α-synuclein phase transitions.

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Protein phase transitions govern numerous diseases, including neurodegenerative disorders. In Parkinson's disease, distinct species of the protein α-synuclein undergo phase transitions from disordered to ordered β-rich states. The emerging species and transitions between them can be reshaped by modulators, e.g., small molecules, peptides or antibodies. Here, we use coarse-grained simulations to understand the effect of modulators on the thermodynamics and kinetics of α-synuclein phase transitions. Each protein is represented as a morphing particle that transforms from a soft sphere (disordered) to a hard spherocylinder (β-rich). Modulators are modeled as soft isotropic particles mimicking peptides. Purely repulsive modulators do not alter the final outcome; that is, fibrils form following the same mechanisms independently of the modulator concentration. Attractive interactions toward the disordered protein dose-dependently slow down fibrillization by stabilizing intermediate species, including persistent disordered heteroclusters. Specific attraction to the β-rich state shortens fibrils through direct modulator surface "capping" that introduces kinetic barriers to monomer templating at the fibril ends and inhibits fibril elongation. Overall, these results link modulator properties and environmental conditions to nucleation, fibril elongation, and off-pathway trapping, providing a quantitative roadmap for designing interventions that redirect phase transitions toward desirable endpoints.

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