Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

PLoS One. 2017 Oct 12;12(10):e0186347. doi: 10.1371/journal.pone.0186347. eCollection 2017.

Abstract

A key player in Alzheimer's disease is the peptide amyloid-beta (Aβ), whose aggregation into small soluble oligomers, protofilaments, and fibrils finally leads to plaque deposits in human brains. The aggregation behavior of Aβ is strongly modulated by the nature and composition of the peptide's environment and by its primary sequence properties. The N-terminal residues of Aβ play an important role, because they are known to change the peptide's aggregation propensity. Since these residues are for the first time completely resolved at the molecular level in a three-fold symmetric fibril structure derived from a patient, we chose that system as template for a systematic investigation of the influence of the N-terminus upon structural stability. Using atomistic molecular dynamics simulations, we examined several fibrillar systems comprising three, six, twelve and an infinite number of layers, both with and without the first eight residues. First, we found that three layers are not sufficient to stabilize the respective Aβ topology. Second, we observed a clear stabilizing effect of the N-terminal residues upon the overall fibril fold: truncated Aβ systems were less stable than their full-length counterparts. The N-terminal residues Arg5, Asp7, and Ser8 were found to form important interfilament contacts stabilizing the overall fibril structure of three-fold symmetry. Finally, similar structural rearrangements of the truncated Aβ species in different simulations prompted us to suggest a potential mechanism involved in the formation of amyloid fibrils with three-fold symmetry.

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Amyloid / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Humans
  • Molecular Dynamics Simulation
  • Protein Stability
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • Amyloid
  • Amyloid beta-Peptides

Grants and funding

AH thanks the Alzheimer Forschung Initiative (AFI) e.V. for a Pilot Grant (16043) to AH, http://www.alzheimer-forschung.de/. The authors acknowledge support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) within the funding programme Open Access Publishing to AH, http://www.dfg.de/, http://www.fau.de/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.