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 journalArticlepeer-review

36 Citations (Scopus)

Abstract

Several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's dis-eases, 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-com-plementing 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 fur-ther 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 destabili-zation 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 help-ful 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
DOIs
Publication statusPublished - Jun 2009

Keywords

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

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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