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

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  • Stefan Auer
  • Filip Meersman
  • Christopher M Dobson
  • Michele Vendruscolo

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.Author Summary: Considerable efforts are currently devoted to the study of the phenomenon of protein aggregation because of its association with a wide variety of human diseases and of its potential applications in biotechnology. Despite intense scrutiny, however, it has been extremely challenging so far to characterise in detail the process by which peptides and proteins aggregate. We have used here molecular simulations to show that the growth of ordered structures from initially disordered assemblies is a consequence of the interplay between two fundamental interactions common to all proteins—hydrophobicity and hydrogen bonding. These results provide further insight into the consequences of the “generic hypothesis” of protein aggregation, according to which the ability to assemble into ordered structures is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but it is an inherent characteristic of polypeptide chains.

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  • Stefan Auer & Filip Meersman & Christopher M Dobson & Michele Vendruscolo, 2008. "A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates," PLOS Computational Biology, Public Library of Science, vol. 4(11), pages 1-7, November.
    • Handle: RePEc:plo:pcbi00:1000222
    DOI: 10.1371/journal.pcbi.1000222
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    References listed on IDEAS

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    1. Mookyung Cheon & Iksoo Chang & Sandipan Mohanty & Leila M Luheshi & Christopher M Dobson & Michele Vendruscolo & Giorgio Favrin, 2007. "Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils," PLOS Computational Biology, Public Library of Science, vol. 3(9), pages 1-12, September.
    2. Dennis J. Selkoe, 2003. "Folding proteins in fatal ways," Nature, Nature, vol. 426(6968), pages 900-904, December.
    3. Christopher M. Dobson, 2003. "Protein folding and misfolding," Nature, Nature, vol. 426(6968), pages 884-890, December.
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    1. Noah S Bieler & Tuomas P J Knowles & Daan Frenkel & Robert Vácha, 2012. "Connecting Macroscopic Observables and Microscopic Assembly Events in Amyloid Formation Using Coarse Grained Simulations," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-10, October.
    2. Sanne Abeln & Michele Vendruscolo & Christopher M Dobson & Daan Frenkel, 2014. "A Simple Lattice Model That Captures Protein Folding, Aggregation and Amyloid Formation," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-8, January.

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