Probling the Principles of Amyloid Formation

探究淀粉样蛋白形成的原理

• 批准号: 6319301
• 负责人: JOHN E. STRAUB
• 金额: $ 30.92万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6319301
• 关键词: amylin; amyloid proteins; chemical aggregate; chemical kinetics; chemical models; dimer; molecular assembly /self assembly; molecular dynamics; protein folding; protein protein interaction; thermodynamics; water solution

DESCRIPTION (provided by applicant): The association of proteins of known sequence is believed to be the principal cause of Alzheimer's and other neurodegenerative diseases. Upon aggregation, certain proteins form fibrillar structures that have been implicated as necessary pathogenic factors. The mechanisms of aggregation of polypeptide chains that lead to the formation of fibrillar structures is largely unknown. To date, experiments have provided only low resolution structures of the aggregated states of certain plaque forming peptides. In addition, the nature of conformational fluctuations leading to aggregation of polypeptide chains has not been fully elucidated. The long-term goal of this research is the elucidation of the fundamental principles responsible for polypeptide association and fibrillar formation. To achieve this goal, the PI's propose a multifaceted approach that includes the development and use of novel computational methods. They will employ all atom molecular dynamics simulations to probe the aggregation mechanism in Abeta-peptide (structured as monomeric peptide in water) and human amylin (structureless in the monomeric state). This will enable them to monitor in detail the nature of initiating (nucleating) structures responsible for fibril formation. The complete characterization of the peptide association pathways will be achieved through the direct simulation of protein-protein association, in conjunction with the application of reaction pathway algorithms to explore protein dimerization and fibril elongation. To discover the general principles governing amyloid formation, Dr. Straub will supplement the detailed molecular dynamics simulations with studies involving coarse grained models of polypeptides. This is necessary due to the prohibitively long times required for all atom simulations to examine a large number of peptide sequences. Using off-lattice and lattice models (with side chains), Dr. Straub proposes to examine the phase behavior, energetics and kinetics of peptide association. A further objective is to probe the role of folding intermediates in facilitating aggregation. Simplified models will be used to examine how the details of peptide sequence and initial conditions influence fibril formation. Preliminary results suggest that both atomistic and coarse-grained models can be effective tools for exploring the details of protein dynamics and equilibriums that arise in the aggregation process. The proposed combination of computational approaches will lead to a conceptual understanding of aggregation, at the molecular level, in polypeptide chains that is central to the understanding of amyloid diseases.

描述（由申请人提供）：已知蛋白质的关联 该序列被认为是阿尔茨海默病和其他疾病的主要原因 神经退行性疾病。聚集后，某些蛋白质形成纤维状 被认为是必要致病因素的结构。这 导致形成的多肽链聚集机制 纤维结构在很大程度上是未知的。迄今为止，实验已经提供 仅某些斑块聚集状态的低分辨率结构 形成肽。此外，构象波动的性质 导致多肽链聚集的原因尚未完全阐明。这 这项研究的长期目标是阐明基本原理 负责多肽缔合和纤维形成的原理。 为了实现这一目标，PI 提出了一种多方面的方法，其中包括 新颖计算方法的开发和使用。他们将雇佣所有人 原子分子动力学模拟探讨聚集机制 Aβ 肽（在水中以单体肽的形式构建）和人胰岛淀粉样多肽 （单体状态下无结构）。这将使他们能够监控 详细描述原纤维起始（成核）结构的性质 形成。肽关联途径的完整表征 将通过直接模拟蛋白质-蛋白质关联来实现， 结合反应路径算法的应用进行探索 蛋白质二聚化和原纤维伸长。发现一般原则 控制淀粉样蛋白的形成，斯特劳布博士将补充详细的分子 动力学模拟与涉及粗粒度模型的研究 多肽。这是必要的，因为所需的时间过长 用于所有原子模拟以检查大量肽序列。使用 离晶格和晶格模型（带有侧链），Straub 博士建议 检查肽缔合的相行为、能量学和动力学。一个 进一步的目标是探讨折叠中间体在促进 聚合。将使用简化模型来检查细节如何 肽序列和初始条件影响原纤维的形成。初步的 结果表明原子模型和粗粒度模型都是有效的 用于探索蛋白质动力学和平衡细节的工具 在聚合过程中。建议的计算组合 方法将导致对聚合的概念性理解， 分子水平，在多肽链中，这是理解的核心 淀粉样蛋白疾病。