6 research outputs found
Aβ(16–22) Peptides Can Assemble into Ordered β‑Barrels and Bilayer β‑Sheets, while Substitution of Phenylalanine 19 by Tryptophan Increases the Population of Disordered Aggregates
A recent experimental study reported
that termini-uncapped Aβ(16–22)
(with sequence KLVFFAE) peptides self-assembled into nanofibrils at
pH 2.0. The oligomerization of this uncapped peptide at atomic level
in acidic pH condition remains to be determined, as computational
studies mainly focus on the self-assembly of capped Aβ(16–22)
peptides at neutral pH condition. In this study, using replica exchange
molecular dynamics (REMD) simulations with explicit solvent, we investigated
the octameric structures of the uncapped AβÂ(16–22) and
its F19W variant at acidic pH condition. Our simulations reveal that
the Aβ(16–22) octamers adopt various conformations, including
closed β-barrels, bilayer β-sheets, and disordered aggregates.
The closed β-barrel conformation is particularly interesting,
as the cylindrical β-barrel has been reported recently as a
cytotoxic species. Interpeptide contact probability analyses between
all pairs of residues reveal that the hydrophobic and aromatic stacking
interactions between F19 residues play an essential role in the formation
of β-barrels and bilayer β-sheets. The importance of F19
and the steric effect on the structures of Aβ(16–22)
octamers are further examined by REMD simulation of F19W mutant. This
REMD run shows that substitution of F19 by W with a more bulky aromatic
side chain significantly reduces the β-sheet content and in
turn enhances the population of disordered aggregates, indicating
that the steric effect significantly affect the self-assembly of low
molecular weight Aβ(16–22) oligomers