期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：21
页码：9490-9495
DOI：10.1073/pnas.0913114107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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+-A{beta} coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn2+ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn2+-A{beta}42, Zn2+ can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn2+-A{beta}42 oligomers and thus enhances their aggregation tendency. Zn2+ 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, Zn2+ 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 Zn2+ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn2+-free solution.
关键词：conformational selection ; energy landscape ; metal ions ; modeling amyloid assemblies ; seed polymorphism
