Probing the Principles Governing Protein Aggregation

探索蛋白质聚集的原理

• 批准号: 7161783
• 负责人: JOHN E. STRAUB
• 金额: $ 37.63万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161783
• 关键词: Address; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloidosis; Area; Behavior; Bioinformatics; Cereals; Characteristics; Charge; Chemicals; Collaborations; Complex; Computing Methodologies; Condition; Development; Dimerization; Disease; Drug Formulations; Electrostatics; Elements; Equilibrium; Event; Goals; Housing; Human; Investigation; Kinetics; Lead; Length; Link; Maps; Modeling; Molecular; Molecular Weight; Morphology; Mutation; Nature; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Pathway interactions; Peptides; Phase; Protein Dynamics; Proteins; Public Health; Range; Rate; Rattus; Research; Research Personnel; Role; Side; Simulate; Site; Son; Structure; Temperature; Testing; Thermodynamics; Time; Urea; Variant; Vertebral column; Work; amyloid formation; base; computer studies; dimer; islet amyloid polypeptide; molecular dynamics; monomer; mutant; neurotoxicity; novel; oxidation; peptide A; polypeptide; protein aggregation; protein folding; response; simulation

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.

描述（由申请人提供）：本提案要求继续进行高效研究，阐明与阿尔茨海默病和其他神经退行性疾病相关的淀粉样蛋白缔合和聚集的基本原理。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疾病的关键。由于有证据表明淀粉样蛋白的可溶性低分子量（LMW）聚集体是神经毒性的主要原因，因此迫切需要了解LMW寡聚体形成的分子机制。还需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肽的构象波动，使其易于聚集。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测导致与阿尔茨海默病相关的淀粉样β-肽和人胰淀素中寡聚体形成的早期事件，其聚集与II型糖尿病有关。该工作有四个具体目标：（1）采用全原子分子动力学模拟来探测淀粉样蛋白β-肽聚集中序列变异的影响。这些研究将绘制这些肽的组装途径，并提供对自然发生的淀粉样蛋白β-肽突变体中观察到的纤维化速率变化的分子水平理解。(2)探索有助于淀粉样β肽寡聚体稳定性的因素，以及相互作用的AP肽对变性剂尿素的反应。(3)关于为什么人胰淀素聚集而大鼠胰淀素不聚集的完整计算研究。β淀粉样蛋白和胰淀素肽结果的比较将为理解肽和蛋白质缔合的序列和环境效应提供概念框架。(4)发现多肽结合的一般原理。详细的分子动力学模拟将补充粗粒度的非晶格模型的多肽。采用具有明确包括序列信息的真实相互作用势的此类模型，将检查肽结合的相行为、能量学和动力学。这项富有成效的研究合作过去的工作表明，原子详细模拟和粗粒度模型研究的混合对于充分探索蛋白质聚集和淀粉样蛋白形成的复杂问题是必要的。与公共卫生相关。拟议的调查将推进淀粉样蛋白p-肽的聚集和重组的研究，涉及阿尔茨海默氏病和其他神经退行性疾病，以及阐明影响胰淀素多肽聚集体形成的因素，涉及II型糖尿病。