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Aminoacid substitutions in the glycine zipper affect the conformational stability of amyloid beta fibrils.

Authors
  • Grasso, Gianvito1
  • Leanza, Luigi2
  • Morbiducci, Umberto2
  • Danani, Andrea1
  • Deriu, Marco A2
  • 1 Dalle Molle Institute for Artificial Intelligence (IDSIA), University of Applied Sciences of Southern Switzerland (SUPSI), University of Italian Switzerland (USI), Manno, Switzerland. , (Switzerland)
  • 2 PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Italy. , (Italy)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
Aug 01, 2020
Volume
38
Issue
13
Pages
3908–3915
Identifiers
DOI: 10.1080/07391102.2019.1671224
PMID: 31543007
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The aggregation of amyloid-beta peptides is associated with the pathogenesis of Alzheimer's disease. The hydrophobic core of the amyloid beta sequence contains a GxxxG repeated motif, called glycine zipper, which involves crucial residues for assuring stability and promoting the process of fibril formation. Mutations in this motif lead to a completely different oligomerization pathway and rate of fibril formation. In this work, we have tested G33L and G37L residue substitutions by molecular dynamics simulations. We found that both protein mutations may lead to remarkable changes in the fibril conformational stability. Results suggest the disruption of the glycine zipper as a possible strategy to reduce the aggregation propensity of amyloid beta peptides. On the basis of our data, further investigations may consider this key region as a binding site to design/discover novel effective inhibitors.Communicated by Ramaswamy H. Sarma.

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