Familial Alzheimer A2 V mutation reduces the intrinsic disorder and completely changes the free energy landscape of the Aβ1-28 monomer

J Phys Chem B. 2014 Jan 16;118(2):501-10. doi: 10.1021/jp4115404. Epub 2014 Jan 7.

Abstract

The self-assembly of the amyloid-β (Aβ) peptide of 39-43 amino acids into senile plaques is one hallmark of Alzheimer's disease (AD) pathology. While A2 V carriers remain healthy in the heterozygous state, they suffer from early onset AD in the homozygous state. As a first toward understanding the impact of A2 V on Aβ at its earlier stage, we characterized the equilibrium ensemble of the Aβ1-28 wild type and Aβ1-28 A2 V monomers by means of extensive atomistic replica exchange molecular dynamics simulations. While global conformational properties such as the radius of gyration and the average secondary structure content of the whole peptides are very similar, the population of β-hairpins is increased by a factor of 4 in A2 V, and this may explain the enhanced Aβ1-40 A2 V aggregation kinetics with respect to Aβ1-40 wild type. Both peptides display a non-negligible population of extended metastable conformations differing however in their atomic details that represent ideal seeds for polymerization. Remarkably, upon A2 V mutation, the intrinsic disorder of Aβ1-28 monomer is reduced by a factor of 2, and the free energy landscape is completely different. This difference in the conformational ensembles of the two peptides may explain in part why the mixture of the Aβ40 WT and A2 V peptides protects against AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Humans
  • Kinetics
  • Light
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutation
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Principal Component Analysis
  • Protein Structure, Secondary
  • Scattering, Radiation
  • Thermodynamics

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-28)
  • amyloid beta-protein (1-40)