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.

β 淀粉样蛋白 (Abeta) 与阿尔茨海默病的病因和发病机制密切相关 （广告）。 Abeta 组装成淀粉样原纤维和更小的寡聚体。我们假设阿贝塔 组装会导致神经元损伤和细胞死亡，从而产生 AD 中观察到的严重脑萎缩。 实验和临床结果表明，Abeta 的寡聚形式可能特别重要。如果是这样， 阐明这些 Abeta 低聚物的结构及其形成机制对于 开发治疗剂。尽管对结构和动力学的实验研究令人印象深刻 Abeta组装，尚未获得充分的了解。我们建议采用计算机方法 成为了解 Abeta 组装及其神经毒性作用的系统策略。该策略涉及一个 反馈 <-> 我们的计算机模拟项目与项目中的其他体外项目之间的前馈协作 授予。我们的计算工具允许以原子分辨率检查 Abeta 寡聚结构。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。粗粒从头开始 DMD Abeta 模型的开发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。我们的目标将通过与 Teplow、Bitan、Benedek 和 Bowers-Shea 团体对 我们对 Abeta 组装的构象、形态、动力学和热力学特征的理解。 这些研究以及其他小组的体外数据将有助于指导该药物的开发 第一代 DMD 方法用于模拟 Abeta 折叠和寡聚物形成。使用第一代 DMD 方法，我们将生成一系列候选寡聚结构（构象异构体）。然后我们将测试 在显式溶剂中使用全原子分子动力学模拟这些构象异构体的稳定性 生理条件。在确定了最稳定的构象异构体后，我们将提出以下假设： 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 由该计划中的其他小组进行体外测试。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 方法的方法。我们随后将 寻求与该计划中的其他小组合作，选择具有潜在毒性的构象异构体。此外， 我们将开发计算机筛选方法来研究 Abeta42（或任何其他肽）与 潜在的寡聚抑制剂，例如 Abeta42 的 C 端片段。这些研究的结果将 是一系列可能用于药物开发以防止 Abeta 寡聚体形成的肽抑制剂。