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Publication Abstract from PubMed

This paper describes the synthesis, solution-phase biophysical studies, and X-ray crystallographic structures of hexamers formed by macrocyclic beta-hairpin peptides derived from the central and C-terminal regions of Abeta, which bear "tails" derived from the N-terminus of Abeta. Soluble oligomers of the beta-amyloid peptide, Abeta, are thought to be the synaptotoxic species responsible for neurodegeneration in Alzheimer's disease. Over the last 20 years, evidence has accumulated that implicates the N-terminus of Abeta as a region that may initiate the formation of damaging oligomeric species. Our laboratory has previously studied macrocyclic beta-hairpin peptides derived from Abeta16-22 and Abeta30-36, capable of forming hexamers that can be observed by X-ray crystallography and SDS-PAGE. To better mimic oligomers of full length Abeta, we use an orthogonal protecting group strategy during the synthesis to append residues from Abeta1-14 to the parent macrocyclic beta not-hairpin peptide 1, which comprises Abeta16-22 and Abeta30-36. The N-terminally extended peptides N+1, N+2, N+4, N+6, N+8, N+10, N+12, and N+14 assemble to form dimers, trimers, and hexamers in solution-phase studies. X-ray crystallography reveals that peptide N+1 assembles to form a hexamer that is composed of dimers and trimers. These observations are consistent with a model in which the assembly of Abeta oligomers is driven by hydrogen bonding and hydrophobic packing of the residues from the central and C-terminal regions, with the N-terminus of Abeta accommodated by the oligomers as an unstructured tail.

Effects of N-Terminal Residues on the Assembly of Constrained beta-Hairpin Peptides Derived from Abeta.,Samdin TD, Wierzbicki M, Kreutzer AG, Howitz WJ, Valenzuela M, Smith A, Sahrai V, Truex NL, Klun M, Nowick JS J Am Chem Soc. 2020 Jun 5. doi: 10.1021/jacs.0c05186. PMID:32501687^[1]

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