Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia, USA.
Biophys J. 2010 Sep 22;99(6):1949-58. doi: 10.1016/j.bpj.2010.07.008.
Although the oligomers formed by Aβ peptides appear to be the primary cytotoxic species in Alzheimer's disease, detailed information about their structures appears to be lacking. In this article, we use exhaustive replica exchange molecular dynamics and an implicit solvent united-atom model to study the structural properties of Aβ monomers, dimers, and tetramers. Our analysis suggests that the conformational ensembles of Aβ dimers and tetramers are very similar, but sharply distinct from those sampled by the monomers. The key conformational difference between monomers and oligomers is the formation of β-structure in the oligomers occurring together with the loss of intrapeptide interactions and helix structure. Our simulations indicate that, independent of oligomer order, the Aβ aggregation interface is largely confined to the sequence region 10-23, which forms the bulk of interpeptide interactions. We show that the fractions of β structure computed in our simulations and measured experimentally are in good agreement.
尽管 Aβ 肽形成的低聚物似乎是阿尔茨海默病中主要的细胞毒性物质，但关于它们的结构的详细信息似乎还缺乏。在本文中，我们使用详尽的复制交换分子动力学和隐溶剂统一原子模型来研究 Aβ 单体、二聚体和四聚体的结构特性。我们的分析表明，Aβ 二聚体和四聚体的构象集合非常相似，但与单体所采样的构象集合明显不同。单体和低聚物之间的关键构象差异是低聚物中β结构的形成，同时伴随着肽内相互作用和螺旋结构的丧失。我们的模拟表明，无论低聚物的顺序如何，Aβ 聚集界面主要局限于序列区域 10-23，该区域形成了大部分肽间相互作用。我们表明，我们模拟计算和实验测量的β结构分数具有很好的一致性。
