Molecular Modeling of Amyloid-beta Oligomer Formation

描述（由申请人提供）：阿尔茨海默病（AD）的神经病理学特征在于形成含有淀粉样β蛋白（ABeta）的细胞外淀粉样斑块和由tau蛋白组成的细胞内神经纤维缠结。ABeta自缔合形成钟形的淀粉样纤维，作为较小的低聚物组装体。这些聚集事件被认为是神经元变性和死亡的基础，其产生在AD中观察到的深度脑萎缩。最近的实验和临床研究结果表明，低聚形式的ABeta可能是关键的神经病理效应在AD。因此，阐明这些ABeta低聚物的结构以开发能够抑制其毒性的药物是至关重要的。尽管令人印象深刻的实验努力，以确定ABeta低聚物的结构，这一目标尚未实现。我们建议开发一种新的计算工具的组合，以确定ABeta低聚物的结构在原子分辨率。这些工具包括高性能的模拟技术，离散分子动力学（DMD），和快速溶剂处理方法，使用全原子分子动力学模拟。我们将开发一个粗粒度的AB到DMD模型的ABeta肽，它考虑到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。我们的目标将通过与D博士的合作实现。B。Teplow的小组，这对我们理解Aft组装的构象，形态，动力学和热力学特征做出了重大贡献。来自Teplow博士研究的体外数据，以及来自其他小组的数据，将有助于限制我们的ABeta寡聚体形成模型。使用这个实验相关的，粗粒度的模型，我们将产生一系列的候选寡聚体结构。然后，我们将使用全原子分子动力学模拟和新开发的方法，在明确的溶剂中的自由能计算在生理条件下测试的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ABeta组装中所起的作用。然后，通过化学合成适当的ABeta肽并研究其组装和神经毒性活性，在Teplow博士的实验室中对这些分析得出的预测进行实验测试。

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.