Yifat Miller

Although a key factor in Alzheimer's disease etiology is enrichment of Zn²⁺ in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn²⁺-Aβ coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn ²⁺ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn ²⁺-Aβ₄₂, Zn²⁺ can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn²⁺- Aβ₄₂ oligomers and thus enhances their aggregation tendency. Zn²⁺ binding does not change the β-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel β-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn²⁺ coordination promotes Aβ₄₂ aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn ²⁺ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn²⁺-free solution.