Probing the Principles Governing Protein Aggregation

描述(由申请人提供)：本提案要求继续进行高效研究，阐明与阿尔茨海默氏症和其他神经退行性疾病相关的淀粉样蛋白关联和聚集的基本原理。长期目标是阐明多肽结合和纤维形成的基本原理，这是我们理解淀粉样蛋白疾病的关键。有证据表明，淀粉样变性蛋白的可溶性低分子量聚集体是神经毒性的主要原因，了解低分子量低聚体形成的分子机制已成为当务之急。还有必要探索外部条件的性质，包括pH、变性剂和温度，这些条件可以驱动单体多肽的构象波动，使它们易于聚集。提出了一种多方面的方法，包括开发和使用新的计算方法来探索导致与阿尔茨海默病相关的淀粉样β多肽和与II型糖尿病有关的人胰淀素的寡聚体形成的早期事件。这项工作有四个具体目标：(1)使用全原子分子动力学模拟来探索序列变异对淀粉样β多肽聚集的影响。这些研究将绘制这些多肽的组装路径图，并从分子水平上了解自然产生的淀粉样β-多肽突变体之间观察到的纤化率的变化。(2)探讨影响淀粉样β-肽低聚体稳定性的因素，以及相互作用的AP-肽对变性尿素的反应。(3)对为什么人的胰淀素聚集，而大鼠的淀粉酶不聚集进行了完整的计算研究。比较淀粉样β蛋白和淀粉样多肽的结果将为理解序列和环境对多肽和蛋白质结合的影响提供一个概念性框架。(4)揭示多肽缔合的一般规律。详细的分子动力学模拟将补充多肽的粗粒非晶格模型。采用这种具有实际相互作用势的模型，其中明确包括序列信息，将考察多肽结合的相行为、能量学和动力学。这一富有成效的研究合作过去的工作表明，混合原子细节模拟和粗粒度模型研究对于全面探索蛋白质聚集和淀粉样蛋白形成的复杂问题是必要的。与公共卫生的相关性。拟议的研究将推进与阿尔茨海默病和其他神经退行性疾病有关的淀粉样β-肽聚集和重组的研究，并阐明与II型糖尿病有关的影响淀粉多肽聚集体形成的因素。

DESCRIPTION (provided by applicant): This proposal is a request to continue highly productive research elucidating the fundamental principles underlying amyloid protein association and aggregation, linked to Alzheimer's Disease and other neurodegenerative disorders. The long-term goal is the formulation of the fundamental principles of polypeptide association and fibril formation, key to our understanding of amyloid disease. As a result of evidence suggesting that soluble low molecular weight (LMW) aggregates of amyloidogenic proteins are the primary cause of neurotoxicity, it has become urgent to understand the molecular mechanisms of formation of LMW oligomers. It is also necessary to explore the nature of external conditions, including pH, denaturant, and temperature that can drive conformational fluctuations in monomeric peptides making them prone to aggregation. A multifaceted approach is proposed that includes the development and use of novel computational methods to probe the early events leading to oligomer formation in Amyloid beta-peptides, linked to Alzheimer's Disease, and human amylin, whose aggregation is implicated in type II diabetes. The effort has four specific aims: (1) Employ all-atom molecular dynamics simulations to probe the effects of sequence variations in the aggregation of Amyloid beta-peptides. These studies will map the assembly pathways in these peptides and provide a molecular-level understanding of the variations in observed fibrillization rates among naturally occurring Amyloid beta-peptide mutants. (2) Explore the factors that contribute to the stability of oligomers of Amyloid beta-peptides, and the response of interacting Ap-peptides to the denaturant urea. (3) Complete computational studies on why human amylin aggregates, while amylin from rats does not. Comparison of results for Amyloid beta and amylin peptides will provide a conceptual framework for understanding sequence and environmental effects on association of peptides and proteins. (4) Discover the general principles of polypeptide association. Detailed molecular dynamics simulations will be supplemented with coarse-grained off-lattice models of polypeptides. Employing such models with realistic interaction potentials that explicitly include sequence information, the phase behavior, energetics, and kinetics of peptide association will be examined. Past work by this productive research collaboration has shown that a blend of atomically detailed simulations and studies of coarse-grained models is necessary to fully explore the complex problem of protein aggregation and amyloid formation. Relevance to Public Health. The proposed investigations will advance the study of the aggregation and reorganization of the amyloid p-peptide, implicated in Alzheimer's Disease, and other neurodegenerative disorders, as well as elucidate the factors that influence the formation of amylin polypeptide aggregates, implicated in type II diabetes.