Zn²⁺ Binding Increases Parallel Structure in the Aβ(16–22) Oligomer by Disrupting Salt Bridge in Antiparallel Structure

The aggregation of monomeric amyloid β protein (Aβ) into oligomers and amyloid plaque in the brain is associated with Alzheimer’s disease. The hydrophobic central core Aβ16–22 has been widely studied due to its essential role in the fibrillization of full-length Aβ peptides. Compared to the homogeneous antiparallel structure of Aβ16–22 at the late stage, the early-stage prefibrillar aggregates contain varying proportions of different β structures. In this work, we studied the appearance probabilities of various self-assembly structures of Aβ16–22 and the effects of Zn2+ on these probabilities by replica exchange molecular dynamics simulations. It was found that at room temperature, Aβ16–22 can readily form assembled β-sheet structures in pure water, where a typical antiparallel arrangement dominates (24.8% of all sampled trimer structures). The addition of Zn2+ to the Aβ16–22 solution will dramatically decrease the appearance probability of antiparallel trimer structures to 12.5% by disrupting the formation of the Lys16–Glu22 salt bridge. Meanwhile, the probabilities of hybrid antiparallel/parallel structures increase. Our simulation results not only reveal the competition between antiparallel and parallel structures in the Aβ16–22 oligomers but also show that Zn2+ can affect the oligomer structures. The results also provide insights into the role of metal ions in the self-assembly of short peptides