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

ABSTRACT

The aggregation of monomeric amyloid ß protein (Aß) into oligomers and amyloid plaque in the brain is associated with Alzheimer's disease. The hydrophobic central core Aß16-22 has been widely studied due to its essential role in the fibrillization of full-length Aß peptides. Compared to the homogeneous antiparallel structure of Aß16-22 at the late stage, the early-stage prefibrillar aggregates contain varying proportions of different ß structures. In this work, we studied the appearance probabilities of various self-assembly structures of Aß16-22 and the effects of Zn2+ on these probabilities by replica exchange molecular dynamics simulations. It was found that at room temperature, Aß16-22 can readily form assembled ß-sheet structures in pure water, where a typical antiparallel arrangement dominates (24.8% of all sampled trimer structures). The addition of Zn2+ to the Aß16-22 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 Aß16-22 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.