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Experiments & Computations to Find Aggregation-Prone Ensembles of Alpha-Synuclein

实验

基本信息

批准号：
7945284
负责人：
JEAN S BAUM
金额：
$ 30.07万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7945284
关键词：
Acetylcysteine Address Adopted Affect Amino Acid Sequence Back Behavior Binding Biological Models Biological Process Boxing Brain C-terminal Chemicals Chimera organism Collaborations Complex Computer Simulation Coupling Data Descriptor Disease Elements Environment Equilibrium Etiology Event Generations Goals Human Imagery Individual Ions Isotope Labeling Joints Label Laboratories Libraries Literature Methods Modeling Molecular Molecular Conformation Mus Mutation N-terminal Nature Neurodegenerative Disorders Parkinson Disease Patients Physics Play Point Mutation Polymers Population Population Distributions Probability Process Property Protein Region Proteins Published Comment Relaxation Reporting Residual state Role Sampling Screening procedure Shapes Simulate Solutions Solvents Staging Structure Technology Testing Thermodynamics Time Variant abstracting alpha synuclein amyloid formation base density design dimer driving force flexibility globular protein inhibitor/antagonist insight monomer mutant polypeptide research study simulation synuclein

项目摘要

DESCRIPTION (provided by applicant): a-synuclein (aSyn) is an intrinsically disordered protein that appears in aggregated form in the brains of patients with Parkinson's disease. The conversion of monomer to aggregate is complex. Aggregation rates of aSyn are very sensitive to changes in amino acid sequence and environmental conditions. Understanding aSyn aggregation requires characterizing the ensemble of conformations adopted by the monomer and correlating them to aggregation behavior. Though many hypotheses have been proposed to relate aSyn's aggregation behavior to its interconverting conformational ensembles, a consistent molecular description of the aSyn conformational ensembles and their relationship to aggregation remains elusive. This proposal integrates NMR and computational approaches to characterize and explicitly visualize the intrinsically disordered conformational ensembles of aSyn and the early stages of aggregation under different sequence and environmental conditions. The goal is to identify the elements of transient 2o and/or 3o structure that are key for initiation of aggregation and determine their stabilizing driving forces. Identifying the structural basis of aSyn monomer aggregation propensity may be critical for developing inhibitors for the aggregation steps that precede the toxic aggregation cascade. Once developed, this integrated approach can be applied to other important biological functions or diseases involving intrinsically disordered proteins. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most prevalent of the late onset neurodegenerative diseases. a-synuclein, an extremely important protein involved in the etiology of Parkinson's disease will be modeled at the molecular level by integrating NMR and computational approaches. Understanding the role of the monomeric conformational ensembles of a-synuclein may be critical for developing inhibition strategies against amyloid formation.

描述（由申请人提供）：α-突触核蛋白（aSyn）是一种内在无序的蛋白质，在帕金森病患者的大脑中以聚集形式出现。单体向聚集体的转化是复杂的。aSyn的聚集速率对氨基酸序列和环境条件的变化非常敏感。理解aSyn聚集需要表征单体所采用的构象集合并将它们与聚集行为相关联。尽管已经提出了许多假设来将aSyn的聚集行为与其相互转换的构象系综相关联，但是aSyn构象系综及其与聚集的关系的一致的分子描述仍然是难以捉摸的。该提案整合了NMR和计算方法，以表征和明确可视化aSyn的固有无序构象集合和在不同序列和环境条件下的早期聚集阶段。我们的目标是确定瞬态的2 o和/或3 o结构的元素，是关键的启动聚集，并确定其稳定的驱动力。鉴定aSyn单体聚集倾向的结构基础对于开发毒性聚集级联之前的聚集步骤的抑制剂可能是至关重要的。一旦开发出来，这种综合方法可以应用于其他重要的生物功能或涉及内在无序蛋白质的疾病。公共卫生相关性：帕金森氏病是第二个最常见的迟发性神经退行性疾病。α-突触核蛋白是参与帕金森病病因学的极其重要的蛋白质，将通过结合NMR和计算方法在分子水平上建模。了解α-突触核蛋白的单体构象集合体的作用对于开发针对淀粉样蛋白形成的抑制策略可能是至关重要的。