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

The aggregation of monomeric amyloid beta protein (A beta) into oligomers and amyloid plaque in the brain is associated with Alzheimer's disease. The hydrophobic central core A beta(16-22) has been widely studied due to its essential role in the fibrillization of full-length A beta peptides. Compared to the homogeneous antiparallel structure of A beta(16-22) at the late stage, the early-stage prefibrillar aggregates contain varying proportions of different beta structures. In this work, we studied the appearance probabilities of various self-assembly structures of A beta(16-22) and the effects of Zn2+ on these probabilities by replica exchange molecular dynamics simulations. It was found that at room temperature, A beta(16-22) can readily form assembled beta-sheet structures in pure water, where a typical antiparallel arrangement dominates (24.8% of all sampled trimer structures). The addition of Zn2+ to the A beta(16-22) 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 A beta(16-22) 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.