Molecular mechanism of misfolding and aggregation of Aβ(13-23)

Sándor Lovas, Yuliang Zhang, Junping Yu, Yuri L. Lyubchenko

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The misfolding and self-assembly of the amyloid-beta (Aβ) peptide into aggregates is a molecular signature of the development of Alzheimer's disease, but molecular mechanisms of the peptide aggregation remain unknown. Here, we combined Atomic Force Microscopy (AFM) and Molecular Dynamics (MD) simulations to characterize the misfolding process of an Aβ peptide. Dynamic force spectroscopy AFM analysis showed that the peptide forms stable dimers with a lifetime of ∼1 s. During MD simulations, isolated monomers gradually adopt essentially similar nonstructured conformations independent from the initial structure. However, when two monomers approach their structure changes dramatically, and the conformational space for the two monomers become restricted. The arrangement of monomers in antiparallel orientation leads to the cooperative formation of β-sheet conformation. Interactions, including hydrogen bonds, salt bridges, and weakly polar interactions of side chains stabilize the structure of the dimer. Under the applied force, the dimer, as during the AFM experiments, dissociates in a cooperative manner. Thus, misfolding of the Aβ peptide proceeds via the loss of conformational flexibility and formation of stable dimers suggesting their key role in the subsequent Aβ aggregation process.

Original languageEnglish (US)
Pages (from-to)6175-6186
Number of pages12
JournalJournal of Physical Chemistry B
Volume117
Issue number20
DOIs
StatePublished - May 23 2013

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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