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Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations

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    Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations
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    International School for Advanced Studies, via Beirut 2-4, Trieste, Italy, CNR-INFM-Democritos National Simulation Center, Beirut 2-4, Trieste, Italy, Italian Institute of Technology - SISSA Unit, via Beirut 2-4, Trieste, Italy, and National Institute for Medical Research, The Ridgeway London, NW71AA, U.K.
    * To whom correspondence should be addressed.
    †International School for Advanced Studies.
    ‡CNR-INFM-Democritos National Simulation Center.
    §Italian Institute of Technology.
    ∥National Institute for Medical Research.
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2008, 112, 51, 16843–16850
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    https://doi.org/10.1021/jp806548p
    Published November 18, 2008
    Copyright © 2008 American Chemical Society
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    Abstract

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    Polyglutamine (polyQ) β-stranded aggregates constitute the hallmark of Huntington disease. The disease is fully penetrant when Q residues are more than 36−40 (“disease threshold”). Here, based on a molecular dynamics study on polyQ helical structures of different shapes and oligomeric states, we suggest that the stability of the aggregates increases with the number of monomers, while it is rather insensitive to the number of Qs in each monomer. However, the stability of the single monomer does depend on the number of side-chain intramolecular H-bonds, and therefore on the number of Qs. If such number is lower than that of the disease threshold, the β-stranded monomers are unstable and hence may aggregate with lower probability, consistently with experimental findings. Our results provide a possible interpretation of the apparent polyQ length dependent-toxicity, and they do not support the so-called “structural threshold hypothesis”, which supposes a transition from random coil to a β-sheet structure only above the disease threshold.

    Copyright © 2008 American Chemical Society

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    Supporting Information

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    Graphs representing the time evolution of RMSD, Rg, secondary structure content and hydrogen bond content for all the systems. The mean values of these properties are also reported in Table 1. A study of the flexibility based on root mean square fluctuation (RMSF) of the large monomeric models is also reported. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cited By

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    This article is cited by 16 publications.

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    14. Vinal V. Lakhani, Feng Ding, Nikolay V. Dokholyan, . Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences. PLoS Computational Biology 2010, 6 (4) , e1000772. https://doi.org/10.1371/journal.pcbi.1000772
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2008, 112, 51, 16843–16850
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jp806548p
    Published November 18, 2008
    Copyright © 2008 American Chemical Society
    Request reuse permissions

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