Wednesday, August 18, 2021 - 11:00am

Abstract: The oligomers formed by the β-amyloid peptide Aβ are unstable and exhibit significant variation in their stoichiometry and structure. This variation complicates efforts to understand how Aβ oligomers affect neurodegeneration associated with Alzheimer’s disease. Frustratingly, high-resolution structures of the oligomers formed by full-length Aβ have largely remained elusive. This thesis describes the development, investigation, and high-resolution structural characterization of three novel macrocyclic β-hairpin peptide model systems, derived from the sequence of Aβ. The first model system incorporates N-terminal residues Aβ1–14 as a tail to a macrocyclic β-hairpin peptide derived Aβ16–22 and Aβ30–36, to examine their effects on oligomer assembly. The second model system, derived from Aβ12–40, assembles to form β-barrel-like tetramers and octamers, and acts to disrupt lipid membranes and facilitate water permeation in molecular dynamics studies. The last model system, derived from Aβ17–23 and Aβ30–36 replaces an N-methyl blocking group, typically used by our laboratory to prevent uncontrolled aggregation, with an α-methyl blocking group to better mimic the hydrogen-bonding edges of endogenous Aβ β-hairpins. Obtaining high-resolution structures of Aβ oligomers and their neurotoxicity will further our understanding of Alzheimer’s disease and holds the promise of bolstering efforts to develop diagnostics and drugs.

Speaker: 

Tuan Samdin

Institution: 

Nowick Group

Location: 

Zoom