Metastable alpha‐rich and beta‐rich conformations of small Aβ42 peptide oligomers

Abstract

Probing the structures of amyloid‐β (Aβ) peptides in the early steps of aggregation is extremely difficult experimentally and computationally. Yet, this knowledge is extremely important as small oligomers are the most toxic species. Experiments and simulations on Aβ42 monomer point to random coil conformations with either transient helical or β‐strand content. Our current conformational description of small Aβ42 oligomers is funneled toward amorphous aggregates with some β‐sheet content and rare high energy states with well‐ordered assemblies of β‐sheets. In this study, we emphasize another view based on metastable α‐helix bundle oligomers spanning the C‐terminal residues, which are predicted by the machine‐learning AlphaFold2 method and supported indirectly by low‐resolution experimental data on many amyloid polypeptides. This finding has consequences in developing novel chemical tools and to design potential therapies to reduce aggregation and toxicity.

Molecular Insights into the Self-Assembly of a Full-Length hIAPP Trimer: β-Protofibril Formed by β-Hairpin Lateral or Longitudinal Association

“…Recently, Berardet et al found that the initial state of conformation, oligomerization, and quality of the hIAPP can greatly impact the aggregation kinetics . Different oligomeric conformations have been predicted using several analytical techniques like TEM, thioflavin T (ThT) fluorescence spectroscopy, or the machine-learning AlphaFold2 method. , …”