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Mutation effects on structural stability of polyglutamine peptides by molecular dynamics simulation

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Abstract

Huntington’s disease patients commonly have glutamine (Q) repeats longer than 37 residues in the Huntingtin protein. This unusual protein will misfold and aggregate to form insoluble amyloid-like fibrils. Although the determination of polyQ structure is very important for elucidation of the aggregation mechanism, this has not yet been accomplished due to the experimental difficulties. In this study, we performed in silico mutation analysis to examine the stability of polyQ peptide on the basis of the β-helix structure which is known as a possible model. From the results of molecular dynamics simulations for 10ns, some mutant models were found to be unstable, and their stabilities were largely dependent on the position of replaced residues. Besides, to examine the relationship between the aggregation mechanism of polyQ and the stability of the corresponding monomer, we constructed trimer models. Through the trimer studies, we confirmed that the stability of the monomer contributes significantly to that of the oligomer, and found that some mutant polyQs have the ability to inhibit polyQ aggregation. Furthermore, we estimated the free energies in solution and the conformational entropic contributions with normal mode analysis. The entropic contributions were not exhibiting remarkable differences between the models under study compared to the differences in the free energies in solution. Supposing that the stability of monomer is associated with aggregation process, the β-helix structure has been found to be somewhat inconsistent with the experimental results in this study. Our results thus indicate the necessity for the revalidation of the β-helix model.

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Abbreviations

polyQ:

polyglutamine

MD:

molecular dynamics

MOE:

Molecular Operating Environment

PBC:

periodic boundary condition

RMSD:

root mean square deviation

RMSF:

root mean square fluctuation

WT:

wildtype

PG pair:

Pro-Gly pair

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Authors and Affiliations

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

    Miki Nakano, Hirofumi Watanabe & Shigenori Tanaka

  2. CREST, Japan Science and Technology Agency, Tokyo, Japan

    Hirofumi Watanabe & Shigenori Tanaka

  3. Institute for Nanotechnology, Research Center of Karlsruhe, PB 3640, D-76021, Karlsruhe, Germany

    E.B. Starikov

  4. Department of Chemistry and Centre for Biotechnology, Brock University, St. Catharines, Ontario, L2S 3A1, Canada

    Stuart M. Rothstein

Authors
  1. Miki Nakano
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  2. Hirofumi Watanabe
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  3. E.B. Starikov
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  4. Stuart M. Rothstein
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  5. Shigenori Tanaka
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Correspondence to Miki Nakano.

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Nakano, M., Watanabe, H., Starikov, E. et al. Mutation effects on structural stability of polyglutamine peptides by molecular dynamics simulation. Interdiscip Sci Comput Life Sci 1, 21–29 (2009). https://doi.org/10.1007/s12539-008-0020-7

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  • DOI: https://doi.org/10.1007/s12539-008-0020-7

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