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 Aβ(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.