Abstract
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.
Original language | English |
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Pages (from-to) | 9490-9495 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 107 |
Issue number | 21 |
DOIs | |
State | Published - 25 May 2010 |
Externally published | Yes |
Keywords
- Energy landscape
- Metal ions
- Modeling amyloid assemblies
- Seed polymorphism
- conformational selection
ASJC Scopus subject areas
- General