Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid β peptide

Liang Kai Chang, Jian Hua Zhao, Hsuan Liang Liu, Kung Tien Liu, Jenn Tzong Chen, Wei Bor Tsai, Yih Ho

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptide GGVVIA from the C-terminal hydrophobic segment of amyloid-β (Aβ) peptide has been determined and revealed a dry, tightly self-complementing structure between two β-sheets, termed as "steric zipper". In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA oligomers with various sizes. The results of our single-layer models suggested that the structural stability of the GGVVIA oligomers increases remarkably with increasing the numbers of β-strands. We further identified that SH2-ST2 may act as a stable seed in prompting amyloid fibril formations. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize and associate the GGVVIA oligomers between β-strands; while the hydrophobic steric zipper formed via the side chains of V3, V4, and I5 plays a critical role in holding the two neighboring β-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two β-sheets, resulting in the destabilization of the oligomers. Our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Aβ peptide.

Original languageEnglish
Pages (from-to)731-740
Number of pages10
JournalJournal of Biomolecular Structure and Dynamics
Volume26
Issue number6
Publication statusPublished - Jun 2009

Fingerprint

Molecular Dynamics Simulation
Amyloid
Peptides
Structural Models
Huntington Disease
Hydrophobic and Hydrophilic Interactions
Neurodegenerative Diseases
Glycine
Parkinson Disease
Seeds
Alzheimer Disease
Water

Keywords

  • Alzheimer's disease
  • Amyloid fibril
  • Amyloid-β peptide
  • Huntington's disease
  • Molecular dynamics simulation
  • Neurodegenerative disease
  • Parkinson's disease
  • Steric zipper

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid β peptide. / Chang, Liang Kai; Zhao, Jian Hua; Liu, Hsuan Liang; Liu, Kung Tien; Chen, Jenn Tzong; Tsai, Wei Bor; Ho, Yih.

In: Journal of Biomolecular Structure and Dynamics, Vol. 26, No. 6, 06.2009, p. 731-740.

Research output: Contribution to journalArticle

Chang, Liang Kai ; Zhao, Jian Hua ; Liu, Hsuan Liang ; Liu, Kung Tien ; Chen, Jenn Tzong ; Tsai, Wei Bor ; Ho, Yih. / Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid β peptide. In: Journal of Biomolecular Structure and Dynamics. 2009 ; Vol. 26, No. 6. pp. 731-740.
@article{9d9f9a54724b416dba0a8794c3c4916a,
title = "Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid β peptide",
abstract = "Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptide GGVVIA from the C-terminal hydrophobic segment of amyloid-β (Aβ) peptide has been determined and revealed a dry, tightly self-complementing structure between two β-sheets, termed as {"}steric zipper{"}. In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA oligomers with various sizes. The results of our single-layer models suggested that the structural stability of the GGVVIA oligomers increases remarkably with increasing the numbers of β-strands. We further identified that SH2-ST2 may act as a stable seed in prompting amyloid fibril formations. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize and associate the GGVVIA oligomers between β-strands; while the hydrophobic steric zipper formed via the side chains of V3, V4, and I5 plays a critical role in holding the two neighboring β-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two β-sheets, resulting in the destabilization of the oligomers. Our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Aβ peptide.",
keywords = "Alzheimer's disease, Amyloid fibril, Amyloid-β peptide, Huntington's disease, Molecular dynamics simulation, Neurodegenerative disease, Parkinson's disease, Steric zipper",
author = "Chang, {Liang Kai} and Zhao, {Jian Hua} and Liu, {Hsuan Liang} and Liu, {Kung Tien} and Chen, {Jenn Tzong} and Tsai, {Wei Bor} and Yih Ho",
year = "2009",
month = "6",
language = "English",
volume = "26",
pages = "731--740",
journal = "Journal of Biomolecular Structure and Dynamics",
issn = "0739-1102",
publisher = "Adenine Press",
number = "6",

}

TY - JOUR

T1 - Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid β peptide

AU - Chang, Liang Kai

AU - Zhao, Jian Hua

AU - Liu, Hsuan Liang

AU - Liu, Kung Tien

AU - Chen, Jenn Tzong

AU - Tsai, Wei Bor

AU - Ho, Yih

PY - 2009/6

Y1 - 2009/6

N2 - Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptide GGVVIA from the C-terminal hydrophobic segment of amyloid-β (Aβ) peptide has been determined and revealed a dry, tightly self-complementing structure between two β-sheets, termed as "steric zipper". In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA oligomers with various sizes. The results of our single-layer models suggested that the structural stability of the GGVVIA oligomers increases remarkably with increasing the numbers of β-strands. We further identified that SH2-ST2 may act as a stable seed in prompting amyloid fibril formations. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize and associate the GGVVIA oligomers between β-strands; while the hydrophobic steric zipper formed via the side chains of V3, V4, and I5 plays a critical role in holding the two neighboring β-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two β-sheets, resulting in the destabilization of the oligomers. Our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Aβ peptide.

AB - Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, are associated with amyloid fibrils formed by different polypeptides. Recently, the atomic structure of the amyloid-forming peptide GGVVIA from the C-terminal hydrophobic segment of amyloid-β (Aβ) peptide has been determined and revealed a dry, tightly self-complementing structure between two β-sheets, termed as "steric zipper". In this study, several all-atom molecular dynamics simulations with explicit water were conducted to investigate the structural stability and aggregation behavior of the GGVVIA oligomers with various sizes. The results of our single-layer models suggested that the structural stability of the GGVVIA oligomers increases remarkably with increasing the numbers of β-strands. We further identified that SH2-ST2 may act as a stable seed in prompting amyloid fibril formations. Our results also demonstrated that hydrophobic interaction is the principle driving force to stabilize and associate the GGVVIA oligomers between β-strands; while the hydrophobic steric zipper formed via the side chains of V3, V4, and I5 plays a critical role in holding the two neighboring β-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two β-sheets, resulting in the destabilization of the oligomers. Our simulation results provided detailed insights into understanding the aggregation behavior of the GGVVIA oligomers in the atomic level. It may also be helpful for designing new inhibitors able to prevent the fibril formation of Aβ peptide.

KW - Alzheimer's disease

KW - Amyloid fibril

KW - Amyloid-β peptide

KW - Huntington's disease

KW - Molecular dynamics simulation

KW - Neurodegenerative disease

KW - Parkinson's disease

KW - Steric zipper

UR - http://www.scopus.com/inward/record.url?scp=67249143457&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67249143457&partnerID=8YFLogxK

M3 - Article

C2 - 19385701

AN - SCOPUS:67249143457

VL - 26

SP - 731

EP - 740

JO - Journal of Biomolecular Structure and Dynamics

JF - Journal of Biomolecular Structure and Dynamics

SN - 0739-1102

IS - 6

ER -