A study of the α-helical intermediate preceding the aggregation of the amino-terminal fragment of the β amyloid peptide (Aβ(1-28))

J Phys Chem B. 2011 Nov 10;115(44):12978-83. doi: 10.1021/jp2050993. Epub 2011 Oct 18.

Abstract

The β amyloid (Aβ) peptide aggregates to form β-rich structures that are known to trigger Alzheimer's disease. Experiments suggest that an α-helical intermediate precedes the formation of these aggregates. However, a description at the molecular level of the α-to-β transition has not been obtained. Because it has been proposed that the transition might be initiated in the amino-terminal region of Aβ, we studied the aggregation of the 28-residue amino-terminal fragment of Aβ (Aβ(1-28)) using molecular dynamics and a coarse-grained force field. Simulations starting from extended and helical conformations showed that oligomerization is initiated by the formation of intermolecular β-sheets between the residues in the N-terminal regions. In simulations starting from the α-helical conformation, forcing residues 17-21 to remain in the initial (helical) conformation prevents aggregation but allows for the formation of dimers, indicating that oligomerization, initiated along the nonhelical N-terminal regions, cannot progress without the α-to-β transition propagating along the chains.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Humans
  • Molecular Dynamics Simulation*
  • Protein Multimerization
  • Protein Stability
  • Protein Structure, Secondary

Substances

  • Amyloid beta-Peptides