Full-Length Molecular Models of Brain-Derived α-Synuclein Fibrils Reveal a Fuzzy-Coat-Mediated Mechanism for Selective Peptide Binding
Parkinsons disease (PD) is characterized by the aggregation of -synuclein (aSyn) into amyloid fibrils that seed further aggregation and contribute to pathological spreading. Peptides that bind aggregated aSyn are promising therapeutic leads, but their validation is slow, difficult to standardize, and often relies on structural models limited to the ordered cross-{beta} core. Here, we built models of brain-derived full-length aSyn fibrils by extending the Lewy-fold cryo-EM structure with disordered N- and C-terminal segments and sampling the resulting ensembles with the CALVADOS coarse-grained force field. The resulting fibrils display a dynamic fuzzy coat in which the termini, especially the acidic C-terminal tails, form recurrent transient contacts with the core, including the aggregation-prone {beta}5 and {beta}9 motifs. We then used these full-length fibrils in a standardized in silico assay for peptide binding. Simulations of the validated peptide binders PSM3 and LL-37 reproduced their relative binding behavior and converged on a common mechanism in which electrostatic capture by the anionic fuzzy coat precedes stabilization on recurrent P2 and P3 hotspots within the structured core. Control simulations with monomeric aSyn or core-only fibrils showed that persistent association is lost in the absence of the full-length architecture, providing a mechanism for selectivity toward aggregated species. Finally, screening 123 peptides from aSynPEP-DB using a relative contact-based binding score yielded a ranked set of candidate binders and identified net positive charge as the dominant determinant of sustained association, with hydrophobicity acting as a secondary modulator. Together, these results establish full-length, brain-derived fibril ensembles as a practical framework for understanding ligand recognition at pathological amyloid surfaces and for prioritizing therapeutic peptide binders targeting aggregated aSyn. SignificanceParkinsons disease is driven by the assembly of -synuclein into amyloid fibrils, yet most structural models of these aggregates omit the disordered termini that form the fibrillar "fuzzy coat" in vivo. Here we use coarse-grained simulations to reconstruct full-length, brain-derived -synuclein fibrils and show that this fuzzy coat transiently contacts the Lewy-fold core, reshaping access to cross-{beta} surface motifs. Using these ensembles in a computational assay, we recapitulate the relative binding behavior of validated peptide inhibitors and reveal a two-step mechanism in which cationic and amphipathic peptides are first captured by the anionic fuzzy coat and then engage recurrent core hotspots. This framework explains selective recognition of aggregated -synuclein and provides a practical route to prioritize therapeutic peptide binders.