Nucleation Process of a Fibril Precursor in the C-Terminal Segment of Amyloid-$\ensuremath{\beta}$

Nucleation Process of a Fibril Precursor in the C-Terminal Segment of Amyloid- $β$

Fahimeh Baftizadeh, Fabio Pietrucci, Xevi Biarnés, and Alessandro Laio

Phys. Rev. Lett. 110, 168103 – Published 17 April 2013

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.