Abstract
Abstract
α‐Synuclein (aSyn) fibrils in Parkinson's disease are generally represented by their ordered cross‐β cores, although nearly half of the protein remains disordered in the fibrillar state. The unresolved N‐ and C‐terminal segments form a fuzzy coat that is expected to shape the surface encountered by molecular partners. Here, we reconstructed full‐length, brain‐derived aSyn Lewy‐fold fibrils by extending a patient‐derived cryo‐EM core spanning residues 31–100, with disordered termini, and sampling the resulting assemblies with the CALVADOS coarse‐grained force field. The acidic C‐terminal tails established recurrent, transient contacts with solvent‐exposed core motifs, especially β5/P2 and β9/P3, generating a dynamic surface in which aggregation‐prone ladders are intermittently shielded rather than permanently buried. Simulations with two experimentally validated aSyn‐binding peptides, PSMα3 and LL‐37, show that peptide recognition follows a two‐step process. Cationic peptides are first retained by the anionic fuzzy coat and subsequently engage exposed hydrophobic/electrostatic hotspots on the structured core. PSMα3 variants and LL‐37 controls support the importance of positive charge for capture, peptide flexibility for multivalent engagement, and the full‐length fibril architecture for persistent binding. These results present a mechanistic model in which selectivity for aggregated aSyn arises from an emergent mesoscale interface combining a polyelectrolyte brush with recurrent core hotspots. Together, these results establish full‐length, brain‐derived fibril ensembles as a practical framework for understanding ligand recognition at amyloid surfaces.