Conformational Ensembles of the Wild-Type and S8C Aβ1-42 Dimers

J Phys Chem B. 2017 Mar 23;121(11):2434-2442. doi: 10.1021/acs.jpcb.7b00267. Epub 2017 Mar 10.

Abstract

We characterized the dimer of the amyloid-β wild-type (WT) peptide, Aβ, of 42 residues and its disulfide-bond-locked double mutant (S8C) by replica exchange molecular dynamics simulations. Aβ dimers are known to be the smallest toxic species in Alzheimer's disease, and the S8C mutant has been shown experimentally to form an exclusive homogeneous and neurotoxic dimer. Our 50 μs all-atom simulations reveal similar secondary structures and collision cross-sections but very different intramolecular and intermolecular conformations upon double S8C mutation. Both dimers are very dynamic with hundreds of free-energy minima that differ from the U-shape and S-shape conformations of the peptides in the fibrils. The only common structural feature, shared by both species with a probability of 4% in WT and 12% in S8C-S8C, is a three-stranded β-sheet spanning the 17-23, 29-36, and 39-41 residues, which does not exist in the Aβ40 WT dimers.

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

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Molecular Dynamics Simulation
  • Mutation
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Multimerization / genetics

Substances

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