A -barrel-like tetramer formed by a -hairpin derived from A
CHEMICAL SCIENCE(2023)
Abstract
beta-Hairpins formed by the beta-amyloid peptide A beta are building blocks of A beta oligomers. Three different alignments of beta-hairpins have been observed in the structures of A beta oligomers or fibrils. Differences in beta-hairpin alignment likely contribute to the heterogeneity of A beta oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of beta-hairpin peptides derived from A beta 12-40 in one of these three alignments and investigated their solution-phase assembly and folding. These assays reveal the formation of tetramers and octamers that are stabilized by intermolecular hydrogen bonding interactions between A beta residues 12-14 and 38-40 as part of an extended beta-hairpin conformation. X-ray crystallographic studies of one peptide from this series reveal the formation of beta-barrel-like tetramers and octamers that are stabilized by edge-to-edge hydrogen bonding and hydrophobic packing. Dye-leakage and caspase 3/7 activation assays using tetramer and octamer forming peptides from this series reveal membrane-damaging and apoptotic properties. A molecular dynamics simulation of the beta-barrel-like tetramer embedded in a lipid bilayer shows membrane disruption and water permeation. The tetramers and octamers described herein provide additional models of how A beta may assemble into oligomers and supports the hypothesis that beta-hairpin alignment and topology may contribute directly to oligomer heterogeneity. beta-Hairpins formed by the beta-amyloid peptide A beta are building blocks of A beta oligomers.
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