Membranes Decouple α-Synuclein Surface Assembly and Kinetic Restriction from Persistent Amyloid-like Intermolecular Organization

Abstract Membrane association places α-synuclein (αSyn) at the boundary between physiological surface organization and pathological amyloid assembly, supporting vesicle clustering, surface condensation, and amyloid nucleation. How interfacial recruitment, condensate cohesion, and persistent amyloid-like organization are coupled or decoupled remains unclear. Because membrane binding also induces helical ordering in the N-terminal membrane-binding region and the aggregation-prone non-amyloid-β component (NAC) region, we used multichain coarse-grained simulations to separate conformational ordering from recruitment by an anionic POPC/POPG bilayer. Helical/ordered segments promoted locally dense, directionally packed assemblies but weakened global condensate cohesion. Membrane association produced flattened surface assemblies and increased the protein population outside the largest condensate. Despite becoming dynamically restricted, these membrane-associated condensates did not show systematically prolonged NAC contact lifetimes. Thus, membrane-driven surface assembly and kinetic restriction can be decoupled from persistent amyloid-like intermolecular organization, explaining how lipid interfaces promote αSyn clustering without necessarily driving amyloid-competent organization.