Sequence-based modeling of Aβ42 soluble oligomers

A beta fibrils, which are central to the pathology of Alzheimer's disease, form a cross beta-structure that contains likely parallel beta-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 A beta forms based on the sequences similarities, assumed to support local structural similarities, of the A beta 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 beta-strands connected by a loop, which contain the Asp23-Lys28 salt bridge. This segment is also structurally well conserved in A beta 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 A beta 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 theorethical data. (c) Wiley Periodicals, Inc.