Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 119, Issue 33, Pages 10478-10487Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.5b05593
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Funding
- Pierre Gilles de Gennes Foundation
- GRAL ANR SIMI [12-BS07-0017-01]
- DYNAMO [ANR-11-LABX-0011]
- IDRIS [x2015077198]
- European Research Council [258748]
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We have studied the diner of amyloid beta peptide A beta of 40 residues by means of all-atom replica exchange molecular dynamics. The A beta-dimers have been found to be the smallest toxic Species in Alzheimer's disease but :their inherent flexibilites have precluded structural characterization by experimental methods. Though the 24-mu s-scale simulation reveals a mean secondary structure of 18% beta-strand and 10% alpha helix we find transient configurations with an unstructured N-terminus and multiple beta-hairpins spanning residues 17-21 and 30-36 but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all alpha topologies and one compact peptide with beta-sheet structure stabilized by a rather extended peptide with alpha-helical content. Overall this first all atom study provides insights into the equilibrium structure of the A beta 1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early stage Alzheimer's disease on a molecular level.
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