Open AccessEffects of N-Terminal Residues on the Assembly of Constrained β-Hairpin Peptides Derived from Aβ
Author(s) -
Tuan D. Samdin,
Michał Wierzbicki,
Adam G. Kreutzer,
William J. Howitz,
Mike Valenzuela,
Alberto Smith,
Victoria Sahrai,
Nicholas L. Truex,
Matthew Klun,
James S. Nowick
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c05186
Subject(s) - random hexamer , chemistry , peptide , oligomer , crystallography , stereochemistry , n terminus , sequence (biology) , c terminus , peptide sequence , amino acid , biochemistry , polymer chemistry , gene
This paper describes the synthesis, solution-phase biophysical studies, and X-ray crystallographic structures of hexamers formed by macrocyclic β-hairpin peptides derived from the central and C-terminal regions of Aβ, which bear "tails" derived from the N-terminus of Aβ. Soluble oligomers of the β-amyloid peptide, Aβ, 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 Aβ as a region that may initiate the formation of damaging oligomeric species. We previously studied, in our laboratory, macrocyclic β-hairpin peptides derived from Aβ 16-22 and Aβ 30-36 , capable of forming hexamers that can be observed by X-ray crystallography and SDS-PAGE. To better mimic oligomers of full length Aβ, we use an orthogonal protecting group strategy during the synthesis to append residues from Aβ 1-14 to the parent macrocyclic β-hairpin peptide 1 , which comprises Aβ 16-22 and Aβ 30-36 . 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 Aβ oligomers is driven by hydrogen bonding and hydrophobic packing of the residues from the central and C-terminal regions, with the N-terminus of Aβ accommodated by the oligomers as an unstructured tail.