Department of Computer Science and Engineering, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi, Aichi 441-8580, Japan.
Murata Manufacturing Co., Ltd., 1-10-1 Higashikotari, Nagaokakyo, Kyoto 617-8555, Japan.
J Mol Graph Model. 2014 May;50:113-24. doi: 10.1016/j.jmgm.2014.03.004. Epub 2014 Apr 16.
The molecular pathogenesis of Alzheimer's disease (AD) is deeply involved in aggregations of amyloid β-proteins (Aβ) in a diseased brain. The recent experimental studies indicated that the mutation of Asp23 by Asn (D23N) within the coding sequence of Aβ increases the risk for the pathogeny of cerebral amyloid angiopathy and early-onset familial ADs. Fibrils of the D23N mutated Aβs can form both parallel and antiparallel structures, and the parallel one is considered to be associated with the pathogeny. However, the structure and the aggregation mechanism of the mutated Aβ fibrils are not elucidated at atomic and electronic levels. We here investigated solvated structures of the two types of Aβ dimers, each of which is composed of the wild-type or the D23N mutated Aβ, using classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods, in order to reveal the effect of the D23N mutation on the structure of Aβ dimer as well as the specific interactions between the Aβ monomers. The results elucidate that the effect of the D23N mutation is significant for the parallel structure of Aβ dimer and that the solvating water molecules around the Aβ dimer have significant contribution to the stability of Aβ dimer.
阿尔茨海默病（AD）的分子发病机制深深涉及到病变大脑中淀粉样β-蛋白（Aβ）的聚集。最近的实验研究表明，Aβ 编码序列中 Asp23 突变为 Asn（D23N）会增加脑淀粉样血管病和早发性家族性 AD 的发病风险。D23N 突变的 Aβ 纤维可以形成平行和反平行结构，平行结构被认为与发病有关。然而，突变的 Aβ 纤维的结构和聚集机制在原子和电子水平上尚未阐明。我们使用经典的分子力学和从头算片段分子轨道（FMO）方法研究了两种 Aβ 二聚体的溶剂化结构，每个二聚体由野生型或 D23N 突变的 Aβ 组成，以揭示 D23N 突变对 Aβ 二聚体结构的影响以及 Aβ 单体之间的特定相互作用。结果表明，D23N 突变对 Aβ 二聚体的平行结构有显著影响，并且 Aβ 二聚体周围的溶剂水分子对 Aβ 二聚体的稳定性有重要贡献。
