AB INITIIO MOLECULAR DYNAMICS OF AB FOLDING AND ASSEMBLY

AB 折叠和组装的从头开始分子动力学

• 批准号: 7119445
• 负责人: H.Eugene STANLEY
• 金额: $ 29.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119445
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; chemical aggregate; chemical models; chemical stability; combinatorial chemistry; computer program /software; computer simulation; inhibitor /antagonist; intermolecular interaction; molecular assembly /self assembly; molecular dynamics; molecular pathology; neuropathology; neuropharmacology; oligopeptides; organic brain syndrome; peptide chemical synthesis; protein folding

The amyloid beta protein (Abeta) has been strongly linked to the etiology and pathogenesis of Alzheimer's disease (AD). Abeta assembles into amyloid fibrils and smaller, oligomeric assemblies. We hypothesize that Abeta assembly leads to neuronal injury and cell death, producing the profound cerebral atrophy observed in AD. Experimental and clinical findings suggest that oligomeric forms of Abeta may be particularly important. If so, elucidation of the structures of these Abeta oligomers and the mechanisms of their formation will be critical for developing therapeutic agents. Despite impressive experimental studies of the structures and dynamics of Abeta assembly, a full understanding has not been obtained. We propose to incorporate an in silico approach into a systematic strategy for understanding Abeta assembly and its neurotoxic effects. This strategy involves a feedback <-> feedforward collaboration between our in silico and other in vitro projects in the program project grant. Our computational tools allow for examination of 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. Coarse-grain ab initio DMD models of Abeta have been developed that take 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 the Teplow, the Bitan, the Benedek, and the Bowers-Shea groups, which have made significant contributions to our understanding of the conformational, morphologic, kinetic, and thermodynamic features of Abeta assembly. The in vitro data from these studies, as well as those from other groups, will help guide development of the first-generation DMD approach to model Abeta folding and oligomer formation. Using this first-generation DMD approach, we will generate a range of candidate oligomeric structures (conformers). We will then test the stability of these conformers using all-atom molecular dynamics simulations in explicit solvent at physiological conditions. After identifying the most stable conformers, we will formulate hypotheses about which amino acids and interactions play the key roles in folding and assembly. These hypotheses will be tested in vitro by the other groups in this program. The results of these in vitro findings will be "fed back" into the DMD approach and will provide means to develop the second-generation DMD approach. We will then seek, in collaboration with the other groups in the program, to select potentially toxic conformers. In addition, we will develop in silico screening methodology to study mixtures of Abeta42 (or any other peptide) with a potential oligomerization inhibitor, such as a C-terminal fragment of Abeta42. The outcome of these studies will be a series of peptide inhibitors of potential use in drug development to prevent Abeta oligomer formation.

淀粉样β蛋白（Abeta）与阿尔茨海默病的病因和发病机制密切相关 （AD）。Abeta组装成淀粉样原纤维和较小的低聚体。我们假设Abeta 组装导致神经元损伤和细胞死亡，产生AD中观察到的严重脑萎缩。 实验和临床研究结果表明，寡聚形式的Abeta可能是特别重要的。如果是这样的话， 这些Abeta寡聚体的结构及其形成机制的阐明将是至关重要的 开发治疗剂。尽管令人印象深刻的实验研究的结构和动力学的 Abeta组装，尚未获得充分理解。我们建议采用计算机模拟方法 为理解Abeta组装及其神经毒性作用提供了一个系统的策略。这一战略涉及一个 我们<->的计算机模拟和其他体外项目之间的反馈前馈协作 格兰特.我们的计算工具允许在原子分辨率下检查Abeta寡聚体结构。这些 工具包括高性能模拟技术、离散分子动力学（DMD）和快速 使用全原子分子动力学模拟的溶剂处理方法。粗晶粒从头算DMD Abeta的模型已经开发出来，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 Teplow，Bitan，Benedek和Bowers-Shea集团，这些集团对 我们对Abeta组装的构象、形态、动力学和热力学特征的理解。 来自这些研究的体外数据，以及来自其他小组的数据，将有助于指导 第一代DMD方法来模拟Abeta折叠和寡聚体形成。使用第一代DMD 方法，我们将产生一系列候选低聚结构（构象异构体）。然后我们将测试 这些构象的稳定性使用全原子分子动力学模拟在明确的溶剂中， 生理条件。在确定了最稳定的构象后，我们将提出关于 哪些氨基酸和相互作用在折叠和组装中起着关键作用。这些假设将是 在这个项目中的其他小组进行了体外测试。这些体外发现的结果将被“反馈”到 DMD方法，并将提供开发第二代DMD方法的手段。然后我们将 寻求与该计划中的其他小组合作，选择潜在有毒的构象。此外，本发明还提供了一种方法， 我们将开发计算机筛选方法来研究Abeta 42（或任何其他肽）与 潜在的寡聚化抑制剂，如Abeta 42的C-末端片段。这些研究的结果将 是一系列潜在用于药物开发以防止Abeta寡聚体形成的肽抑制剂。