Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 21, Pages 9490-9495Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913114107
Keywords
conformational selection; energy landscape; metal ions; modeling amyloid assemblies; seed polymorphism
Categories
Funding
- National Cancer Institute, NIH [HHSN261200800001E]
- NIH, National Cancer Institute, Center for Cancer Research
Ask authors/readers for more resources
Although a key factor in Alzheimer's disease etiology is enrichment of Zn(2+) in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn(2+)-A beta 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+)-A beta(42), Zn(2+) can simultaneously coordinate intra-and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn(2+)-A beta(42) oligomers and thus enhances their aggregation tendency. Zn(2+) binding does not change the beta-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 beta-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn(2+) coordination promotes A beta(42) 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 Zn(2+)-free solution.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available