The possible structural models for polyglutamine aggregation: A molecular dynamics simulations study

Zheng Li Zhou, Jian Hua Zhao, Hsuan Liang Liu, Josephine W. Wu, Kung Tien Liu, Chih Kuang Chuang, Wei Bor Tsai, Yih Ho

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial β-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung β-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high β-turn and β-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable β-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of β-turn and β-sheet are sampled and preserved during the very early stage of aggregation.

Original languageEnglish
Pages (from-to)743-758
Number of pages16
JournalJournal of Biomolecular Structure and Dynamics
Volume28
Issue number5
Publication statusPublished - Apr 2011

Fingerprint

Structural Models
Molecular Dynamics Simulation
Huntington Disease
Glutamine
Neurodegenerative Diseases
polyglutamine
Seeds

Keywords

  • β-helix
  • Aggregation
  • Huntington's disease
  • Molecular dynamics simulations
  • Nucleation
  • Polyglutamine (polyQ)

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

The possible structural models for polyglutamine aggregation : A molecular dynamics simulations study. / Zhou, Zheng Li; Zhao, Jian Hua; Liu, Hsuan Liang; Wu, Josephine W.; Liu, Kung Tien; Chuang, Chih Kuang; Tsai, Wei Bor; Ho, Yih.

In: Journal of Biomolecular Structure and Dynamics, Vol. 28, No. 5, 04.2011, p. 743-758.

Research output: Contribution to journalArticle

Zhou, ZL, Zhao, JH, Liu, HL, Wu, JW, Liu, KT, Chuang, CK, Tsai, WB & Ho, Y 2011, 'The possible structural models for polyglutamine aggregation: A molecular dynamics simulations study', Journal of Biomolecular Structure and Dynamics, vol. 28, no. 5, pp. 743-758.
Zhou, Zheng Li ; Zhao, Jian Hua ; Liu, Hsuan Liang ; Wu, Josephine W. ; Liu, Kung Tien ; Chuang, Chih Kuang ; Tsai, Wei Bor ; Ho, Yih. / The possible structural models for polyglutamine aggregation : A molecular dynamics simulations study. In: Journal of Biomolecular Structure and Dynamics. 2011 ; Vol. 28, No. 5. pp. 743-758.
@article{0e1e3e41816b41c192fa78dd84d5c589,
title = "The possible structural models for polyglutamine aggregation: A molecular dynamics simulations study",
abstract = "Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial β-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung β-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high β-turn and β-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable β-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of β-turn and β-sheet are sampled and preserved during the very early stage of aggregation.",
keywords = "β-helix, Aggregation, Huntington's disease, Molecular dynamics simulations, Nucleation, Polyglutamine (polyQ)",
author = "Zhou, {Zheng Li} and Zhao, {Jian Hua} and Liu, {Hsuan Liang} and Wu, {Josephine W.} and Liu, {Kung Tien} and Chuang, {Chih Kuang} and Tsai, {Wei Bor} and Yih Ho",
year = "2011",
month = "4",
language = "English",
volume = "28",
pages = "743--758",
journal = "Journal of Biomolecular Structure and Dynamics",
issn = "0739-1102",
publisher = "Adenine Press",
number = "5",

}

TY - JOUR

T1 - The possible structural models for polyglutamine aggregation

T2 - A molecular dynamics simulations study

AU - Zhou, Zheng Li

AU - Zhao, Jian Hua

AU - Liu, Hsuan Liang

AU - Wu, Josephine W.

AU - Liu, Kung Tien

AU - Chuang, Chih Kuang

AU - Tsai, Wei Bor

AU - Ho, Yih

PY - 2011/4

Y1 - 2011/4

N2 - Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial β-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung β-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high β-turn and β-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable β-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of β-turn and β-sheet are sampled and preserved during the very early stage of aggregation.

AB - Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion near the N-terminus of huntingtin. Previous studies have suggested that polyQ aggregation occurs only when the number of glutamine (Q) residues is more than 36-40, the disease threshold. However, the structural characteristics of polyQ nucleation in the very early stage of aggregation still remain elusive. In this study, we designed 18 simulation trials to determine the possible structural models for polyQ nucleation and aggregation with various shapes and sizes of initial β-helical structures, such as left-handed circular, right-handed rectangular, and left- and right-handed triangular. Our results show that the stability of these models significantly increases with increasing the number of rungs, while it is rather insensitive to the number of Qs in each rung. In particular, the 3-rung β-helical models are stable when they adopt the left-handed triangular and right-handed rectangular conformations due to the fact that they preserve high β-turn and β-sheet contents, respectively, during the simulation courses. Thus, we suggested that these two stable β-helical structures with at least 3 rungs might serve as the possible nucleation seeds for polyQ depending on how the structural elements of β-turn and β-sheet are sampled and preserved during the very early stage of aggregation.

KW - β-helix

KW - Aggregation

KW - Huntington's disease

KW - Molecular dynamics simulations

KW - Nucleation

KW - Polyglutamine (polyQ)

UR - http://www.scopus.com/inward/record.url?scp=79952209980&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952209980&partnerID=8YFLogxK

M3 - Article

C2 - 21294586

AN - SCOPUS:79952209980

VL - 28

SP - 743

EP - 758

JO - Journal of Biomolecular Structure and Dynamics

JF - Journal of Biomolecular Structure and Dynamics

SN - 0739-1102

IS - 5

ER -