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

TitleConformational Ensembles of the Wild-Type and S8C Aβ1-42 Dimers.
Publication TypeJournal Article
Year of Publication2017
AuthorsMan VHoang, Nguyen PH, Derreumaux P
JournalJ Phys Chem B
Volume121
Issue11
Pagination2434-2442
Date Published2017 Mar 23
ISSN1520-5207
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.

DOI10.1021/acs.jpcb.7b00267
Alternate JournalJ Phys Chem B
Citation Key2017|2032
PubMed ID28245647