title: Molecular dynamics simulations to investigate the structural stability and aggregation behavior of the GGVVIA oligomers derived from amyloid beta 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-beta (Abeta) peptide has been determined and revealed a dry, tightly self-complementing structure between two beta-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 beta-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 beta-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 beta-sheets together. Single glycine substitution at V3, V4, and I5 directly disrupted the hydrophobic steric zipper between these two beta-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 Abeta peptide.
authors.affiliation: Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei 10608, Taiwan.
authors.forename: Liang-Kai
authors.initials: LK
authors.lastname: Chang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Hsuan-Liang
authors.initials: HL
authors.lastname: Liu
authors.forename: Kung-Tien
authors.initials: KT
authors.lastname: Liu
authors.forename: Jenn-Tzong
authors.initials: JT
authors.lastname: Chen
authors.forename: Wei-Bor
authors.initials: WB
authors.lastname: Tsai
authors.forename: Yih
authors.initials: Y
authors.lastname: Ho
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments