A β-barrel-like tetramer formed by a β-hairpin derived from Aβ

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Beta-amyloid (Aβ) beta-hairpins are fundamental units of Aβ oligomers.
• Observed variations in beta-hairpin alignment within Aβ oligomers contribute to structural heterogeneity, complicating high-resolution studies.

Purpose of the Study:

• To design and synthesize Aβ-derived beta-hairpin peptides mimicking a specific alignment.
• To investigate the solution-phase assembly, folding, and structural characteristics of these peptides.
• To assess the biological activity, including membrane interaction and apoptotic potential, of the resulting oligomeric structures.

Main Methods:

• Peptide design and synthesis based on Aβ12-40.
• Solution-phase assembly and folding assays.
• X-ray crystallography for structural determination.
• Dye-leakage and caspase 3/7 activation assays.
• Molecular dynamics simulations of peptide-lipid interactions.

Main Results:

• Synthesized peptides self-assembled into stable tetrameric and octameric structures.
• These oligomers were stabilized by intermolecular hydrogen bonds (Aβ residues 12-14 and 38-40) and hydrophobic packing.
• X-ray crystallography revealed beta-barrel-like structures for tetramers and octamers.
• Oligomers demonstrated membrane-damaging capabilities and induced caspase 3/7 activation, indicating apoptotic effects.
• Molecular dynamics simulations confirmed membrane disruption and water permeation by the tetrameric structure.

Conclusions:

• The designed beta-hairpin peptides serve as valuable models for studying Aβ oligomer formation.
• The observed tetrameric and octameric structures provide insights into Aβ assembly pathways.
• Beta-hairpin alignment and topology are critical factors contributing to the heterogeneity of Aβ oligomers.