SIMULATION OF AB OLIGOMER INTERACTION WITH MEMBRANES

AB 低聚物与膜相互作用的模拟

• 批准号: 8224272
• 负责人: markus desemo
• 金额: $ 13.94万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224272
• 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; Computer Simulation; Constitution; Data; Dementia; Development; Drug Delivery Systems; Drug Formulations; Electrophysiology (science); Etiology; Event; Federal Government; Fluorescence; Freedom; Generic Drugs; Hydrophobicity; Ion Channel; Knowledge; Lateral; Lead; Length; Link; Lipid Bilayers; Lipids; Maps; Measures; Mediating; 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; Toxic effect; 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(AD)是一种毁灭性的神经退行性疾病，是痴呆症的主要原因。它 目前影响到500多万美国人，估计每年给联邦政府造成的总成本为1500亿美元 以及州政府和企业。其发病机制与淀粉样蛋白的堆积有关。 大脑中的β(AB)蛋白。最近的几条证据有力地支持了小分子可溶性AB 低聚物，而不是纤维状聚集体，是真正的神经毒性物种，但它们确切的作用模式 仍然不为人知。这项研究方案是在AP寡聚体吸附到细胞上的假设下进行的 膜，从而干扰其正常的生物功能，如电绝缘。我们的长期合作 目的了解AP-膜相互作用及其与AD病因学的关系。在目前的研究中 将开发项目计算技术和模型，目的是获得结构信息 关于AB分布，揭示了它们与膜的协同作用模式，并辅助 对合作项目的实验结果进行解释。涉及的长度和时间尺度都很大 在AB聚合中，需要粗粒度的模拟方法，但定量链接需要 结合了更精细的比例细节。因此，我们成功研究的理由将围绕以下几个方面进行设计 多尺度方法。具体地说，我们的目标是(I)在我们的粗粒膜中重新引入化学细节 模型，(Ii)将现有的CG多肽模型与我们改进的CGIS双层模型相结合，从而 定量研究AB多肽与膜的相互作用，以及(III)大规模合作研究 AP低聚体在膜上的聚集及其对双层分子组织的反作用。 这些目标将从与实验的紧密合作和频繁的知识传授中受益匪浅 该PPG的同事通过提供与中子反射仪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，在该PPG内开发的工具进行了集体优化。从长远来看，这项研究将有助于 了解阿尔茨海默病的分子基础。它有助于识别新的药物靶点，可能防止 在可察觉的症状出现之前很久，有害的分子过程就出现了，从而使 得到及时的治疗。