Miller Yifat, Ma Buyong, Nussinov Ruth
Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9490-5. doi: 10.1073/pnas.0913114107. Epub 2010 May 6.
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+)-Abeta 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+)-Abeta(42), Zn(2+) can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn(2+)-Abeta(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 Abeta(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.
尽管阿尔茨海默病病因中的一个关键因素是聚集体中锌离子（Zn(2+)）的富集，并且有数据表明锌会促进聚集，但Zn(2+)与β-淀粉样蛋白（Aβ）的配位如何促进聚集仍不清楚。在这里，我们探究了Zn(2+)影响淀粉样变性的结构和机制。通过共价连接片段（这些片段具有基于实验的坐标），我们观察到，在寡聚的Zn(2+)-Aβ(42)中，Zn(2+)可以同时进行分子内和分子间配位，连接两个肽段。锌配位显著降低了大的Zn(2+)-Aβ(42)寡聚体的溶剂化能，从而增强了它们的聚集倾向。Zn(2+)结合不会改变C端疏水区域周围的β-折叠关联；然而，它改变了预先存在的淀粉样多态体集合的相对丰度。结果，虽然平行β-折叠排列仍然是首选，但反平行和其他结构较少的聚集体得到了稳定，也成为了主要类型。总体而言，Zn(2+)配位促进了Aβ(42)聚集，导致结构的均匀性降低。我们的副本交换分子动力学模拟进一步重现了一个实验观察结果，即增加Zn(2+)浓度会减慢聚集速率，尽管聚集速率仍远高于无Zn(2+)溶液中的速率。
