title: Nucleation process of a fibril precursor in the C-terminal segment of amyloid-β.
abstract: By extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-β, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent" fibril may differ from the one of an "extended" fibril.
authors.affiliation: SISSA, via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Fahimeh
authors.initials: F
authors.lastname: Baftizadeh
authors.forename: Fabio
authors.initials: F
authors.lastname: Pietrucci
authors.forename: Xevi
authors.initials: X
authors.lastname: Biarnés
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laio
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments