Blinov Nikolay, Khorvash Massih, Wishart David S, Cashman Neil R, Kovalenko Andriy
Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta T6G 1H9, Canada.
National Institute for Nanotechnology, National Research Council of Canada, Edmonton, Alberta T6G 2M9, Canada.
ACS Omega. 2017 Nov 7;2(11):7621-7636. doi: 10.1021/acsomega.7b00805. eCollection 2017 Nov 30.
Experimental characterization of the molecular structure of small amyloid (A)β oligomers that are currently considered as toxic agents in Alzheimer's disease is a formidably difficult task due to their transient nature and tendency to aggregate. Such structural information is of importance because it can help in developing diagnostics and an effective therapy for the disease. In this study, molecular simulations and protein-protein docking are employed to explore a possible connection between the structure of Aβ monomers and the properties of the intermonomer interface in the Aβ42 dimer. A structurally diverse ensemble of conformations of the monomer was sampled in microsecond timescale implicit solvent replica exchange molecular dynamics simulations. Representative structures with different solvent exposure of hydrophobic residues and secondary structure content were selected to build structural models of the dimer. Analysis of these models reveals that formation of an intramonomer salt bridge (SB) between Asp23 and Lys28 residues can prevent the building of a hydrophobic interface between the central hydrophobic clusters (CHCs) of monomers upon dimerization. This structural feature of the Aβ42 dimer is related to the difference in packing of hydrophobic residues in monomers with the Asp23-Lys28 SB in on and off states, in particular, to a lower propensity to form hydrophobic contacts between the CHC domain and C-terminal residues in monomers with a formed SB. These findings could have important implications for understanding the difference between aggregation pathways of Aβ monomers leading to neurotoxic oligomers or inert fibrillar structures.
目前被认为是阿尔茨海默病中毒性因子的小淀粉样蛋白（A）β寡聚体的分子结构实验表征是一项极其艰巨的任务，因为它们具有瞬态性质且易于聚集。此类结构信息很重要，因为它有助于开发该疾病的诊断方法和有效治疗方法。在本研究中，采用分子模拟和蛋白质 - 蛋白质对接来探索Aβ单体结构与Aβ42二聚体中单体间界面性质之间的可能联系。在微秒时间尺度的隐式溶剂复制交换分子动力学模拟中对单体构象的结构多样集合进行了采样。选择具有不同疏水残基溶剂暴露和二级结构含量的代表性结构来构建二聚体的结构模型。对这些模型的分析表明，Asp23和Lys28残基之间形成的单体内部盐桥（SB）可以阻止二聚化时单体中心疏水簇（CHC）之间形成疏水界面。Aβ42二聚体的这一结构特征与具有开启和关闭状态的Asp23 - Lys28 SB的单体中疏水残基堆积的差异有关，特别是与具有形成的SB的单体中CHC结构域和C末端残基之间形成疏水接触的较低倾向有关。这些发现可能对理解导致神经毒性寡聚体或惰性纤维状结构的Aβ单体聚集途径之间的差异具有重要意义。
