Folding and membrane insertion of amyloid-beta (25-35) peptide and its mutants: Implications for aggregation and neurotoxicity

Hui Hsu Gavin Tsai, Jian Bin Lee, Sheng Shiuan Tseng, Xiao An Pan, Yuan Ci Shih

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The mechanisms of interfacial folding and membrane insertion of the Alzheimer's amyloid-β fragment Aβ(25-35) and its less toxic mutant, N27A-Aβ(25-35) and more toxic mutant, M35A-Aβ(25-35), are investigated using replica-exchange molecular dynamics in an implicit water-membrane environment. This study simulates the processes of interfacial folding and membrane insertion in a spontaneous fashion to identify their general mechanisms. Aβ(25-35) and N27A-Aβ(25-35) peptides share similar mechanisms: the peptides are first located in the membrane hydrophilic region where their C-terminal residues form helical structures. The peptides attempt to insert themselves into the membrane hydrophobic region using the C-terminal or central hydrophobic residues. A small portion of peptides can successfully enter the membrane's hydrophobic core, led by their C-terminal residues, through the formation of continuous helical structures. No detectable amount of M35A-Aβ(25-35) peptides appeared to enter the membrane's hydrophobic core. The three studied peptides share a similar helical structure for their C-terminal five residues, and these residues mainly buried within the membrane's hydrophobic region. In contrast, their N-terminal properties are markedly different. With respect to the Aβ(25-35), the N27A-Aβ(25-35) forms a more structured helix and is buried deeper within the membrane, which may result in a lower degree of aggregation and a lower neurotoxicity; in contrast, the less structured and more water-exposed M35A-Aβ(25-35) is prone to aggregation and has a higher neurotoxicity. Understanding the mechanisms of Aβ peptide interfacial folding and membrane insertion will provide new insights into the mechanisms of neurodegradation and may give structurebased clues for rational drug design preventing amyloid associated diseases.

Original languageEnglish
Pages (from-to)1909-1925
Number of pages17
JournalProteins: Structure, Function and Genetics
Volume78
Issue number8
DOIs
StatePublished - Jun 2010

Keywords

  • Aggregation
  • Amyloid-beta
  • Interfacial folding
  • Membrane insertion
  • Neurotoxicity
  • Replica-exchange molecular dynamics

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