Probing the Principles Governing Protein Aggregation

探索蛋白质聚集的原理

• 批准号: 7319662
• 负责人: JOHN E. STRAUB
• 金额: $ 36.56万
• 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/7319662
• 关键词: Address; Alzheimer' s Disease; Amino Acids; Amyloidosis; Area; Behavior; Bioinformatics; Cereals; Characteristics; Charge; Chemicals; Collaborations; Complex; Computing Methodologies; Condition; Development; Dimerization; Disease; Electrostatics; Elements; Equilibrium; Event; Goals; Housing; Human; Hydrochloride Salt; 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; Range; Rate; Rattus; Research; Research Personnel; Role; Side; Simulate; Site; Son; Structure; Temperature; Testing; Thermodynamics; Time; Urea; Variant; Vertebral column; Work; amyloid formation; amyloid peptide; base; computer studies; dimer; guanidinium; islet amyloid polypeptide; molecular dynamics; monomer; mutant; neurotoxicity; novel; oxidation; peptide A; polypeptide; protein aggregation; protein folding; response; simulation

This proposal is a request to continue highly productive research directed at elucidating the fundamental principles underlying amyloid peptide association and aggregation. Aggregation of proteins of known sequence is linked to Alzheimer'sDisease (AD) and other neurodegenerative disorders. Because recent evidence strongly suggests that soluble low molecular weight (LMW) aggregates of amyloidogenic proteins are the primary cause of neurotoxicity, there is urgency in understandingthe molecular mechanisms of LMW oligomer formation. In addition, it is necessary to elucidate the nature of external conditions, including pH, denaturant, and temperature, that can drive conformational fluctuations in the monomeric peptides that make them prone to aggregation. The,long-term goal of the proposed effort is to formulate the fundamental principlesresponsible for polypeptide association and fibril formation. To achieve this goal, 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 A(3-peptides, linked to AD, and human amylin, whose aggregation is implicated in type II diabetes. The effort is comprised of projects directed at four specific aims: (1) All-atom molecular dynamics simulations will be used to probe the effects of sequence variations in the aggregation of A0-peptides. These studies will lead to a map of the assembly pathways in these peptides, as well as provide a molecular-level understandingof the variations in the observed fibrillization rates among naturallyoccurring Ap-peptide mutants. (2) To dissect the factors that contribute to the stability of oligomers of A|3-peptides, the response of interacting Ap-peptides to denaturants, such as urea and guanidinium hydrochloride, will be explored. (3) Computational studies to understand why human amylin aggregates, while amylin from rats does not will be completed. By comparing the results for Ap and amylin peptides, a conceptual framework for understanding sequence and environmentaleffects on association of peptides and proteins will be developed. (4) To discover the general principles of polypeptide association, the detailed moleculardynamics simulations will be supplemented with studies involving coarse-grained off-lattice models of polypeptides. Employingsuch 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 the productive research collaboration has shown that combining atomically detailed simulations and studies of coarse-grained models has the potential to fully explore the complex problem of amyloid formation. These proposed studies will lead to a conceptual understanding of peptide aggregation, at the molecular level, that is central to the understandingof amyloid diseases.

这项建议是要求继续进行富有成效的研究，以阐明基本原则， 淀粉样肽缔合和聚集。已知序列的蛋白质聚集与阿尔茨海默病（AD）有关 和其他神经退行性疾病。因为最近的证据强烈表明，可溶性低分子量（LMW） 淀粉样蛋白的聚集是神经毒性的主要原因，迫切需要了解其分子机制。 LMW低聚物形成的机制。此外，有必要阐明外部条件的性质，包括pH值， 变性剂和温度，这可以驱动单体肽的构象波动，使它们易于 聚合来这项工作的长期目标是阐明多肽的基本原理， 缔合和原纤维形成。 为了实现这一目标，提出了一种多方面的方法，包括开发和使用新的计算 方法探测导致A β-肽中寡聚体形成的早期事件，与AD和人胰淀素连接， 聚集与II型糖尿病有关。这一努力由针对四个具体目标的项目组成： 分子动力学模拟将用于探测A0-肽聚集中序列变异的影响。这些 研究将导致这些肽的组装途径的地图，以及提供分子水平的理解， 在自然发生的AP-肽突变体之间观察到的絮凝率的变化。(2)剖析那些 有助于A的低聚物的稳定性|3-肽，相互作用的AP-肽对变性剂如尿素和 盐酸胍，将被探索。(3)计算研究，以了解为什么人类胰淀素聚集，而 来自大鼠的胰淀素不会完成。通过比较Ap和胰淀素肽的结果， 了解序列和环境对肽和蛋白质结合的影响。(4)来发现 多肽协会的一般原则，详细的分子动力学模拟将补充研究 涉及多肽的粗粒度非晶格模型。采用具有真实相互作用势的模型， 明确地包括序列信息，将检查肽缔合的相行为、能量学和动力学。 生产性研究合作的过去工作表明，将原子详细模拟和对 粗粒模型具有充分探索淀粉样蛋白形成的复杂问题的潜力。这些拟议的研究将 导致在分子水平上对肽聚集的概念性理解，这是理解淀粉样蛋白的核心 疾病