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. © 2013 American Physical Society.
|Titolo:||Nucleation process of a fibril precursor in the C-terminal segment of amyloid-beta|
|Autori:||Baftizadeh, F; Pietrucci, F; Biarnés, X; Laio, A|
|Rivista:||PHYSICAL REVIEW LETTERS|
|Data di pubblicazione:||2013|
|Digital Object Identifier (DOI):||10.1103/PhysRevLett.110.168103|
|Appare nelle tipologie:||1.1 Journal article|