Sequence‐based modeling of Aβ42 soluble oligomers

Aβ fibrils, which are central to the pathology of Alzheimer's disease, form a cross‐β‐structure that contains likely parallel β‐sheets with a salt bridge between residues Asp23 and Lys28. Recent studies suggest that soluble oligomers of amyloid peptides have neurotoxic effects in cell cultures, raising the interest in studying the structures of these intermediate forms. Here, we present three models of possible soluble Aβ forms based on the sequences similarities, assumed to support local structural similarities, of the Aβ peptide with fragments of three proteins (adhesin, Semliki Forest virus capsid protein, and transthyretin). These three models share a similar structure in the C‐terminal region composed of two β‐strands connected by a loop, which contain the Asp23‐Lys28 salt bridge. This segment is also structurally well conserved in Aβ fibril forms. Differences between the three monomeric models occur in the N‐terminal region and in the C‐terminal tail. These three models might sample some of the most stable conformers of the soluble Aβ peptide within oligomeric assemblies, which were modeled here in the form of dimers, trimers, tetramers, and hexamers. The consistency of these models is discussed with respect to available experimental and theoretical data. © 2007 Wiley Periodicals, Inc. Biopolymers 85: 422–437, 2007. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com