SIMULATION OF AB OLIGOMER INTERACTION WITH MEMBRANES

AB 低聚物与膜相互作用的模拟

• 批准号: 8020071
• 负责人: markus desemo
• 金额: $ 13.47万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8020071
• 关键词: 20 year old; Affect; Alzheimer' s Disease; American; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Autopsy; Back; Biochemical; Biological Process; Brain; Businesses; Cell membrane; Cereals; Cessation of life; Chemicals; Collaborations; Computational Technique; Constitution; Data; Dementia; Development; Drug Delivery Systems; Drug Formulations; Electrophysiology (science); Etiology; Event; Fluorescence; Freedom; Generic Drugs; Hydrophobicity; Ion Channel; Knowledge; Lateral; Lead; Length; Link; Lipid Bilayers; Lipids; Maps; Measures; Membrane; Methods; Modeling; Molecular; Nature; Neurodegenerative Disorders; Neutrons; Pathogenesis; Peptides; Physics; Physiological; Positioning Attribute; Process; Reaction; Research; Research Personnel; Research Project Grants; Research Proposals; Resolution; Senile Plaques; Severities; Shapes; Simulate; Solvents; Specificity; Spectrum Analysis; State Government; Structure; Symptoms; System; Techniques; Time; Work; abeta accumulation; amyloid peptide; base; cost; cytotoxicity; design; electric impedance; experience; improved; membrane model; molecular dynamics; monomer; neurotoxic; prevent; protein aggregation; research study; simulation; spatiotemporal; tool

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia. It currently affects over five million Americans, and incurs an estimated $150 billion total annual costs to Federal and State Government and Business. Its pathogenesis has been related to the accumulation of amyloid beta (AB) protein in the brain. Several recent lines of evidence strongly support the idea that small soluble AB oligomers, rather than fibrillar aggregates, are the actual neurotoxic species, but their precise mode of action remains unknown. This research proposal operates under the hypothesis that Ap oligomers adsorb onto cell membranes and thereby interfer with their normal biological function, e.g. electrical insulation. Our long-term objective is to understand Ap-membrane interactions and relate them to AD etiology. In the present research project computational techniques and models will be developed with the aim to obtain structural information about AB distribution, uncover their cooperative mode of interaction with the membrane, and aid the interpretation of experimental results from the partner projects. The large length- and time-scales involved in AB aggregation require a coarse-grained simulation approach, but a quantitative link calls for the incorporation of finer scale detail. Our rationale for a successful research will therefore be designed around multiscaling methods. Specifically, we aim to (i) re-introduce chemical detail into our coarse-grained membrane model, (ii) Combine an existing CG peptide model with our improved CGIS bilayer model and thereby quantitatively study the interaction of AB peptides with membranes, and (iii) study the large-scale cooperative aggregation of AP oligomers on membranes and their back effect on the molecular organization of the bilayer. These aims will benefit strongly from a tight cooperation and a frequent knowledge transfer with experimentally working colleagues in this PPG by offering a comparison with data measured in neutron reflectometry, fluorescence cross-correlation spectroscopy, electrophysiology and impedance spectroscopy. Tools developed Within this PPG are thus collectively optimized. In the long term this research will contribute to an understanding of the molecular basis of AD. It helps to identify new drug targets that might prevent the detrimental molecular processes long before noticeable symptoms materialize, thereby enabling possibilities of a timely treatment.

阿尔茨海默病（Alzheimer's disease，AD）是一种严重的神经退行性疾病，是痴呆的主要病因。它 目前影响着500多万美国人，估计每年给联邦政府带来1500亿美元的总成本。 州政府和企业。其发病机制与淀粉样蛋白的积累有关 B（AB）蛋白在大脑中的作用最近的一些证据有力地支持了小可溶性AB 低聚物，而不是纤维状聚集体，是实际的神经毒性物质，但它们的确切作用方式 仍然未知。这项研究计划的假设下运作的Ap寡聚体吸附到细胞 膜，从而干扰其正常的生物功能，例如电绝缘。我们的长期 目的是了解AP-膜相互作用，并将其与AD病因学联系起来。目前研究中 为了获得结构信息，将开发项目计算技术和模型 关于AB分布，揭示它们与膜相互作用的合作模式，并帮助 对合作伙伴项目的实验结果进行解释。所涉及的大的长度和时间尺度 在AB聚合中，需要粗粒度的模拟方法，但定量链接需要 更精细尺度细节的结合。因此，我们成功研究的基本原理将围绕 多尺度方法具体来说，我们的目标是（i）重新引入化学细节到我们的粗粒度膜 模型，（ii）将现有的CG肽模型与我们改进的CGIS双层模型相结合，从而 定量研究AB肽与膜的相互作用，和（iii）研究大规模的合作 AP低聚物在膜上的聚集及其对双层分子组织的反向影响。 这些目标将大大受益于紧密的合作和频繁的知识转让与实验 通过与中子反射计测量的数据进行比较， 荧光互相关光谱、电生理学和阻抗光谱。 因此，在此PPG内开发的工具得到了共同优化。从长远来看，这项研究将有助于 对AD的分子基础的理解。它有助于确定新的药物靶点， 在明显症状出现之前，有害的分子过程就会发生， 及时的治疗。