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A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates

Auer, S., Meersman, F., Dobson, C.M., Vendruscolo, M. and Nussinov, R. (2008) A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates. PLoS Computational Biology, 4 (11). e1000222. ISSN 1553-7358

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Abstract

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention because it has been associated with a range of neurodegenerative conditions including Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate that the formation of ordered arrays of hydrogen bonds drives the formation of β-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Individual β-sheets initially form with random orientations and subsequently tend to align into protofilaments as their lengths increase. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first-order phase transitions by showing that ordered cross-β structures emerge preferentially from disordered compact dynamical intermediate assemblies.

Item Type: Article
Copyright, Publisher and Additional Information: © 2008 Auer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institution: The University of Leeds
Academic Units: The University of Leeds > University of Leeds Research Centres and Institutes > Centre for Self-Organising Molecular Systems (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 06 Nov 2009 15:02
Last Modified: 15 Sep 2014 04:08
Published Version: http://dx.doi.org/10.1371/journal.pcbi.1000222
Status: Published
Publisher: Public Library of Science
Identification Number: doi: 10.1371/journal.pcbi.1000222
URI: http://eprints.whiterose.ac.uk/id/eprint/10096

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