Full-length brain-derived α-synuclein fibril models reveal fuzzy-coat control of peptide recognition.

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.