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

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-beta, 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. DOI: 10.1103/PhysRevLett.110.168103


Published in:
Physical Review Letters, 110, 16
Year:
2013
Publisher:
College Pk, Amer Physical Soc
ISSN:
0031-9007
Laboratories:




 Record created 2013-10-01, last modified 2018-09-13


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