Molecular Modeling of Amyloid-beta Oligomer Formation

描述（由申请人提供）：阿尔茨海默病（AD）的神经病理学特征是细胞外淀粉样斑块的形成，其中含有淀粉样β蛋白（ABeta）和细胞内由蛋白tau组成的神经原纤维缠结。自结合形成淀粉样蛋白原纤维，如小的钟状低聚体。这些聚集事件被认为是阿尔茨海默病中观察到的产生深度脑萎缩的神经元变性和死亡的基础。最近的实验和临床发现表明，寡聚形式的β可能是AD的关键神经发病效应物。因此，阐明这些β寡聚物的结构是至关重要的，以便开发能够抑制其毒性的药物。尽管在确定β低聚物结构方面的实验努力令人印象深刻，但这一目标尚未实现。我们建议开发一种新的计算工具组合，以确定在原子分辨率的β寡聚物结构。这些工具包括高性能模拟技术、离散分子动力学（DMD）和使用全原子分子动力学模拟的快速溶剂处理方法。我们将开发一个粗粒度的ABeta肽的DMD模型，该模型考虑了主链氢键相互作用以及侧链之间的氨基酸特异性相互作用。我们的目标将与D. B. Teplow博士的团队合作实现，他们对我们理解Aft组装的构象、形态、动力学和热力学特征做出了重大贡献。特普罗博士的体外研究数据，以及其他研究小组的数据，将有助于限制我们的β寡聚物形成模型。使用这个实验相关的粗粒度模型，我们将生成一系列候选的低聚物结构。然后，我们将使用全原子分子动力学模拟和新开发的自由能计算方法在生理条件下显式溶剂中测试低聚物构象的稳定性。稳定结构的鉴定将使我们开始了解特定氨基酸在控制β组装中所起的作用。从这些分析中得出的预测将在Teplow博士的实验室进行实验测试，通过化学合成适当的β肽，并研究它们的组装和神经毒性活性。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized neuropathologically by formation of extracellular amyloid plaques containing the amyloid Beta-protein (ABeta) and intracellular neurofibrillary tangles composed of the protein tau. ABeta self-associates to form amyloid fibrils as bell as smaller, oligomeric assemblies. These aggregation events are thought to underlie the neuronal degeneration and death that produces the profound cerebral atrophy observed in AD. Recent experimental and clinical findings suggest that oligomeric forms of ABeta may be the key neuropathogenetic effectors in AD. It is therefore critical to elucidate the structures of these ABeta oligomers in order to develop pharmaceuticals capable of inhibiting their toxicity. Despite impressive experimental efforts to determine the structures of ABeta oligomers, this goal has not yet been attained. We propose to develop a novel combination of computational tools to determine ABeta oligomeric structures at atomic resolution. These tools include a high-performance simulation technique, discrete molecular dynamics (DMD), and a rapid solvent treatment methodology using all-atom molecular dynamics simulations. We will develop a coarse-grained ab into DMD model of the ABeta peptide which takes into account main-chain hydrogen bond interactions as well as amino acid-specific interactions between side chains. Our aims will be achieved in collaboration with Dr. D. B. Teplow's group, which has made significant contributions to our understanding of the conformational, morphologic, kinetic, and thermodynamic features of Aft assembly. The in vitro data from Dr. Teplow's studies, as well as those from other groups, will help constrain our model of ABeta oligomer formation. Using this experimentally relevant, coarse-grained model, we will generate a range of candidate oligomeric structures. We then will test the stability of the oligomer conformations using all-atom molecular dynamics simulations and newly-developed methodology for free-energy calculations in an explicit solvent at physiological conditions. The identification of stable structures will allow us to begin to understand the roles specific amino acids play in controlling ABeta assembly. Predictions emanating from these analyses then will be tested experimentally in Dr. Teplow's laboratory through chemical synthesis of appropriate ABeta peptides and study of their assembly and neurotoxic activity.