Mancini Onorio, Rolinski Olaf J, Kubiak-Ossowska Karina, Mulheran Paul A
Department of Chemical and Process Engineering, University of Strathclyde, Glasgow G1 1XJ, U.K.
Department of Physics, University of Strathclyde, Glasgow G4 0NG, U.K.
ACS Omega. 2018 Nov 27;3(11):16046-16056. doi: 10.1021/acsomega.8b02408. eCollection 2018 Nov 30.
During the early stages of β amyloid (Ab) peptide aggregation, toxic oligomers form which have been recognized as a likely cause of Alzheimer's disease. In this work, we use fully atomistic molecular dynamics simulation to study the amorphous aggregation of the peptide as well as model β-sheet protofibril structures. In particular, we study the rotamer states of the single fluorescent tyrosine (Tyr) residue present in each Ab. We find that the occupation of the four previously identified rotamers is different for monomeric and amorphous aggregates because of the differing environments of the Tyr side-chains. Surprisingly, we also identify two new rotamers that uniquely appear for the β-sheet structures, so that together the rotamers provide distinct signatures for the different stages of aggregation and fibrillation. We propose that these rotamers could be identified in fluorescence spectroscopy, with each rotamer having a distinct fluorescence lifetime because of its different exposures to the solvent. The identification of the two new rotamers therefore provides a new means to probe amyloid formation kinetics and to monitor the effect of additives including prospective drugs.
在β淀粉样蛋白（Ab）肽聚集的早期阶段，会形成有毒的寡聚体，这些寡聚体被认为是阿尔茨海默病的一个可能病因。在这项工作中，我们使用全原子分子动力学模拟来研究该肽的无定形聚集以及模型β-折叠原纤维结构。特别是，我们研究了每个Ab中存在的单个荧光酪氨酸（Tyr）残基的旋转异构体状态。我们发现，由于Tyr侧链所处环境不同，四种先前确定的旋转异构体在单体和无定形聚集体中的占据情况有所不同。令人惊讶的是，我们还识别出两种新的旋转异构体，它们仅在β-折叠结构中出现，因此这些旋转异构体为聚集和纤维化的不同阶段提供了独特的特征。我们提出，这些旋转异构体可以在荧光光谱中被识别出来，由于它们对溶剂的暴露程度不同，每个旋转异构体都有独特的荧光寿命。因此，这两种新旋转异构体的识别为探测淀粉样蛋白形成动力学以及监测包括潜在药物在内的添加剂的效果提供了一种新方法。
