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Publication Abstract from PubMed

The supramolecular assembly of amyloid-beta into soluble oligomers is critical Alzheimer's disease (AD) progression. Soluble Abeta oligomers have emerged as neurotoxic species involved in AD progression and some Abeta oligomers are thought to be composed of beta-hairpins. In this work, we report the X-ray crystallographic and solution-phase assembly of a macrocyclic beta-hairpin peptide that mimics a beta-hairpin formed by Abeta(16-36). In the crystal lattice, the peptide assembles into a symmetric hexamer composed of two identical triangular trimers. In aqueous solution, the peptide assembles to form an asymmetric hexamer. (1)H NMR, TOCSY, and (1)H,(15)N HSQC experiments establish that the asymmetric hexamer contains two different species, A and B. (15)N-edited NOESY reveals that species A is a cylindrin-like trimer and species B is a triangular trimer that collectively constitute the asymmetric hexamer. Diffusion-ordered NMR spectroscopy (DOSY) suggests that two asymmetric hexamers further assemble to form a dodecamer. NMR-guided molecular mechanics and molecular dynamics studies provide a model for the asymmetric hexamer and suggest how two asymmetric hexamers can form a dodecamer. Solution-phase NMR studies of analogues show that intermolecular hydrogen bonding and the formation of a hydrophobic core help stabilize the asymmetric hexamer. These NMR and crystallographic studies illustrate how an Abeta beta-hairpin peptide can assemble to form different well-defined oligomers in the crystal state and in aqueous solution, providing a deeper understanding of the heterogeneity of Abeta oligomers and new structural models of Abeta oligomers composed of Abeta beta-hairpins.

A beta-hairpin peptide derived from Abeta forms different oligomers in the crystal state and in aqueous solution.,Zhu J, Kreutzer AG, Liu Z, Li X, Richter SM, Pophristic V, Nowick JS Org Biomol Chem. 2025 Mar 25. doi: 10.1039/d5ob00296f. PMID:40130612^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.