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.

这项提议是要求继续进行高产出的研究，旨在阐明基本原则 淀粉样多肽的缔合和聚集。已知序列的蛋白质聚集与阿尔茨海默病(AD)有关 以及其他神经退行性疾病。因为最近的证据有力地表明，可溶性低分子量(LMW) 淀粉样蛋白聚集体是神经毒性的主要原因，迫切需要了解分子 低分子低聚物的形成机理。此外，有必要阐明外部条件的性质，包括pH， 变性剂和温度，这会导致单体多肽的构象波动，使它们容易 聚合。拟议工作的长期目标是制定多肽的基本原理 联结和原纤维的形成。 为了实现这一目标，提出了一种多方面的方法，其中包括开发和使用新颖的计算 方法探讨与AD相关的A(3-肽)和人胰淀素形成寡聚的早期事件。 聚集与II型糖尿病有关。这项努力包括针对四个具体目标的项目：(1)全原子 分子动力学模拟将被用来探索序列变异对A0-肽聚集的影响。这些 研究将导致绘制这些多肽的组装路径图，并提供对分子水平的了解 观察到的纤化率在自然发生的AP-肽突变体中的差异。(2)剖析影响经济发展的因素 有助于A|3-肽低聚体的稳定性，相互作用的AP-肽对变性剂的反应，如尿素和 将对盐酸胍进行勘探。(3)计算研究，以了解为什么人类胰淀素聚集，而 大鼠的胰淀素不会被完成。通过比较AP和Amylin多肽的结果，一个概念框架 了解序列和环境对多肽和蛋白质结合的影响。(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研究 涉及多肽的粗粒非晶格模型。采用这种具有现实交互潜力的模型 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。 Productive Research Collaboration过去的工作表明，结合原子详细的模拟和研究 粗粒度模型有可能充分探索淀粉样蛋白形成的复杂问题。这些拟议的研究将 在分子水平上对多肽聚集有一个概念性的理解，这是理解淀粉样蛋白的核心。 疾病。