Metastable Alpha-rich and Beta-rich Conformations of Small Aβ42
Peptide Oligomers
Phuong H. Nguyen,1 Fabio Sterpone,1Philippe Derreumaux 1,2*
1 CNRS, Université Paris Cité, UPR 9080, Laboratoire de Biochimie
Théorique, Institut de Biologie Physico-Chimique, Fondation Edmond de
Rothschild, 13 rue Pierre et Marie Curie, 75005 Paris, France.
2 Institut Universitaire de France (IUF), 75005, Paris, France.
Abstract: Probing the structures of amyloid-beta (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 excited 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-terminus 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 designing drugs to reduce
aggregation and toxicity.
Keywords: amyloid-beta, aggregation, simulations, atomistic,
coarse-grained, small oligomers