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