Pathways of Alzehimer's amyloid assembly studied by computer simulations

通过计算机模拟研究阿尔茨海默淀粉样蛋白组装途径

• 批准号: 7292146
• 负责人: DMITRI Konstantinovich KLIMOV
• 金额: $ 20.5万
• 依托单位: GEORGE MASON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292146
• 关键词: Algorithms; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Cereals; Computer Simulation; Deposition; Dissociation; Docking; Event; Free Energy; Growth; Image; Individual; Investigation; Kinetics; Knowledge; Methods; Microscopic; Modeling; Molecular; Molecular Biology; Morphologic artifacts; Pathway interactions; Peptides; Pharmaceutical Preparations; Physical Chemistry; Play; Process; Property; Proteins; Reporting; Research; Research Personnel; Role; Sampling; Solvents; Temperature; Thermodynamics; Validation; Work; abeta accumulation; abeta oligomer; amyloid formation; amyloidogenesis; base; computer science; design; dimer; molecular dynamics; molecular modeling; monomer; neurotoxic; novel; novel strategies; parallel computing; peptide A; research study; simulation; single molecule

DESCRIPTION (provided by investigator ): According to amyloid hypothesis the assembly of Abeta peptides into fibrils plays a central role in Alzheimer's disease. Recent experiments suggest that not only Abeta amyloid fibrils, but also Abeta oligomers are potent neurotoxic agents. However, due to complexity of amyloid assembly the associated molecular mechanisms remain poorly understood. The current proposal targets two distinct mechanisms of Alzheimer's amyloidogenesis - the formation of Abeta oligomers and the elongation of preexisting Abeta fibrils by deposition of individual peptides. The main questions of the project are how do these mechanisms of Alzheimer's amyloidogenesis manifest themselves on a single molecule level? Is it possible to develop a combined microscopic description of fibril growth and oligomer assembly, which together represent major events in Abeta amyloidogenesis? What is the molecular basis of anti-aggregation effect produced by certain non-steroidal anti-inflammatory drugs (NSAID)? To answer these questions a molecular model of the pathways of Abeta amyloid assembly will be developed. The proposed work relies on high-end parallel computing and multi-scale molecular modeling. To overcome computational challenges new protein model and new sampling algorithms are employed. Cross-validation strategies to reduce computational artifacts are incorporated in the research plan. The biomedical significance of the proposed work is that the knowledge of molecular mechanisms of Abeta aggregation can be used to devise strategies to control the levels of soluble and fibrillized Abeta peptides. In particular, the project findings will be useful in the design of new NSAID derivatives with stronger anti-aggregation propensity and Abeta imaging efficiency.

描述（由研究者提供）：根据淀粉样蛋白假说，A β肽组装成原纤维在阿尔茨海默病中起着重要作用。 最近的实验表明，不仅Abeta淀粉样纤维，而且Abeta寡聚体是有效的神经毒性剂。 然而，由于淀粉样蛋白组装的复杂性，相关的分子机制仍然知之甚少。 目前的提案针对阿尔茨海默氏症淀粉样变性的两种不同机制--Abeta寡聚体的形成和通过单个肽的沉积延长预先存在的Abeta原纤维。 该项目的主要问题是阿尔茨海默氏症淀粉样蛋白生成的这些机制如何在单分子水平上表现出来？ 是否有可能开发一个组合的纤维生长和寡聚体组装，共同代表在A β淀粉样蛋白的主要事件的显微镜描述？ 某些非甾体抗炎药（NSAID）产生抗聚集作用的分子基础是什么？ 为了回答这些问题，将开发一种Abeta淀粉样蛋白组装途径的分子模型。 所提出的工作依赖于高端并行计算和多尺度分子建模。 为了克服计算的挑战，新的蛋白质模型和新的采样算法。 交叉验证策略，以减少计算文物纳入研究计划。 所提出的工作的生物医学意义在于，Abeta聚集的分子机制的知识可用于设计策略来控制可溶性和固定化Abeta肽的水平。 特别是，该项目的发现将有助于设计具有更强抗聚集倾向和Abeta成像效率的新NSAID衍生物。