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

描述(申请人提供)：A-突触核蛋白(ASyn)是一种内在的无序蛋白质，在帕金森氏症患者的大脑中以聚集的形式出现。单体向聚集体的转化是复杂的。ASyn的聚集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联系起来，但对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。这一建议结合了核磁共振和计算方法来表征和显式可视化aSyn的内在无序构象集合以及在不同序列和环境条件下的早期聚集阶段。目标是确定瞬变的2O和/或3O结构的元件，这些元件是引发聚集的关键，并确定它们的稳定驱动力。确定aSyn单体聚集倾向的结构基础对于开发有毒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，这种集成的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：帕金森氏病是晚发型神经退行性疾病中第二常见的疾病。A-突触核蛋白是参与帕金森氏病病因学的一种极其重要的蛋白质，它将通过结合核磁共振和计算方法在分子水平上进行模拟。了解a-突触核蛋白单体构象系综的作用可能对开发抑制淀粉样蛋白形成的策略至关重要。

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.