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Study of the aggregation mechanism of polyglutamine peptides using replica exchange molecular dynamics simulations

Journal of Molecular Modeling volume 19, pages 1627–1639 (2013)Cite this article

Abstract

Polyglutamine (polyQ, a peptide) with an abnormal repeat length is the causative agent of polyQ diseases, such as Huntington’s disease. Although glutamine is a polar residue, polyQ peptides form insoluble aggregates in water, and the mechanism for this aggregation is still unclear. To elucidate the detailed mechanism for the nucleation and aggregation of polyQ peptides, replica exchange molecular dynamics simulations were performed for monomers and dimers of polyQ peptides with several chain lengths. Furthermore, to determine how the aggregation mechanism of polyQ differs from those of other peptides, we compared the results for polyQ with those of polyasparagine and polyleucine. The energy barrier between the monomeric and dimeric states of polyQ was found to be relatively low, and it was observed that polyQ dimers strongly favor the formation of antiparallel β-sheet structures. We also found a characteristic behavior of the monomeric polyQ peptide: a turn at the eighth residue is always present, even when the chain length is varied. We previously showed that a structure including more than two sets of β-turns is stable, so a long monomeric polyQ chain can act as an aggregation nucleus by forming several pairs of antiparallel β-sheet structures within a single chain. Since the aggregation of polyQ peptides has some features in common with an amyloid fibril, our results shed light on the mechanism for the aggregation of polyQ peptides as well as the mechanism for the formation of general amyloid fibrils, which cause the onset of amyloid diseases.

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Abbreviations

Q:

Glutamine

polyQ:

Polyglutamine

MD:

Molecular dynamics

REMD:

Replica exchange molecular dynamics

MMD:

Multiple molecular dynamics

CD:

Circular dichroism

DPSS:

Dictionary of protein secondary structure

apβ:

Antiparallel β-sheet

pβ:

Parallel β-sheet

D min :

The minimum distance between the Cα atoms of the monomers (except for both termini)

Λ mono :

Distance from the Cα atom of the C-terminus to that of the N-terminus

\( n_{\mathrm{Hbond}}^{\mathrm{inter}} \) :

The number of intermolecular hydrogen bonds between two molecules

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Acknowledgments

We thank Dr. Takatoshi Fujita for useful comments and discussions. The numerical calculations were partially carried out on a PC-cluster system in the Cybermedia Center at Osaka University.

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Affiliations

  1. Graduate School of Human Development and Environment, Kobe University, 3-11, Tsurukabuto, Nada, Kobe, 657-8501, Japan

    Miki Nakano & Kuniyoshi Ebina

  2. Graduate School of System Informatics, Department of Computational Science, Kobe University, 1-1, Rokkodai, Nada, Kobe, 657-8501, Japan

    Shigenori Tanaka

Authors
  1. Miki Nakano
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  2. Kuniyoshi Ebina
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  3. Shigenori Tanaka
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Correspondence to Miki Nakano or Shigenori Tanaka.

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Nakano, M., Ebina, K. & Tanaka, S. Study of the aggregation mechanism of polyglutamine peptides using replica exchange molecular dynamics simulations. J Mol Model 19, 1627–1639 (2013). https://doi.org/10.1007/s00894-012-1712-9

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  • DOI: https://doi.org/10.1007/s00894-012-1712-9

Keywords

  • Polyglutamine disease
  • Protein aggregation
  • Protein folding
  • Free-energy landscape
  • Replica exchange molecular dynamics simulation
  • Amyloid fibril