Cheon Mookyung, Favrin Giorgio, Chang Iksoo, Dobson Christopher M, Vendruscolo Michele
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Front Biosci. 2008 May 1;13:5614-22. doi: 10.2741/3104.
Protein misfolding and aggregation are associated with a range of severe human neurodegenerative conditions. We use all-atom simulations to describe the process of assembly of the Abeta(16-22) and Abeta(25-35) fragments of Abeta, a peptide associated with Alzheimer's disease. Our results indicate that the pathways of aggregation of these two peptides depend predominantly on the relative strength of hydrophobic interactions and hydrogen bonding. In the Abeta(25-35) peptide, which is weakly hydrophobic, the tendency to form hydrogen bonds drives the crossing of a single major free energy barrier for the formation of a cross-beta structure. By contrast, in the more hydrophobic Abeta(16-22) peptide, the process of ordered assembly is preceded by an initial collapse into disordered oligomers. These results provide support for a recently proposed two-step mechanism of amyloid formation. We have also found that the barriers for reordering are lower for large oligomers than for small oligomers, a result that provides an explanation of the recent experimental observation that the efficiency of the seeding reaction depends on the size of the seeds themselves.
蛋白质错误折叠和聚集与一系列严重的人类神经退行性疾病相关。我们使用全原子模拟来描述与阿尔茨海默病相关的β-淀粉样蛋白（Aβ）的Aβ(16 - 22)和Aβ(25 - 35)片段的组装过程。我们的结果表明，这两种肽的聚集途径主要取决于疏水相互作用和氢键的相对强度。在疏水性较弱的Aβ(25 - 35)肽中，形成氢键的倾向驱动了形成交叉β结构时跨越单个主要自由能垒的过程。相比之下，在疏水性更强的Aβ(16 - 22)肽中，有序组装过程之前是先坍缩成无序的低聚物。这些结果为最近提出的淀粉样蛋白形成的两步机制提供了支持。我们还发现，大的低聚物重新排序的能垒比小的低聚物低，这一结果解释了最近的实验观察结果，即种子反应的效率取决于种子本身的大小。
