Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer

Biophys J. 2012 Jan 18;102(2):315-24. doi: 10.1016/j.bpj.2011.12.002.


The aggregation of amyloid beta (Aβ) peptides plays an important role in the development of Alzheimer's disease. Despite extensive effort, it has been difficult to characterize the secondary and tertiary structure of the Aβ monomer, the starting point for aggregation, due to its hydrophobicity and high aggregation propensity. Here, we employ extensive molecular dynamics simulations with atomistic protein and water models to determine structural ensembles for Aβ(42), Aβ(40), and Aβ(42)-E22K (the Italian mutant) monomers in solution. Sampling of a total of >700 microseconds in all-atom detail with explicit solvent enables us to observe the effects of peptide length and a pathogenic mutation on the disordered Aβ monomer structural ensemble. Aβ(42) and Aβ(40) have crudely similar characteristics but reducing the peptide length from 42 to 40 residues reduces β-hairpin formation near the C-terminus. The pathogenic Italian E22K mutation induces helix formation in the region of residues 20-24. This structural alteration may increase helix-helix interactions between monomers, resulting in altered mechanism and kinetics of Aβ oligomerization.

Publication types

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

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics*
  • Markov Chains
  • Molecular Dynamics Simulation*
  • Mutation*
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics*
  • Protein Multimerization*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Time Factors
  • Water / chemistry


  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Water