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Probling the Principles of Amyloid Formation

探究淀粉样蛋白形成的原理

基本信息

批准号：
6729854
负责人：
JOHN E. STRAUB
金额：
$ 27.6万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2005-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6729854
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

项目摘要

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）：已知的蛋白质的缔合序列被认为是阿尔茨海默氏症和其他疾病的主要原因。神经退行性疾病在聚集时，某些蛋白质形成纤维状，这些结构被认为是必要的致病因素。的多肽链的聚集机制，导致形成纤维状结构在很大程度上是未知的。迄今为止，实验提供了只有某些斑块的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。的这项研究的长期目标是阐明基本的负责多肽缔合和纤维形成的原理。为了实现这一目标，PI提出了一个多方面的方法，包括新的计算方法的开发和使用。他们将雇用所有原子分子动力学模拟探讨聚集机制， A β-肽（在水中作为单体肽结构化）和人胰淀素（在单体状态下无结构）。这将使他们能够监测详细说明了引发（成核）结构的性质，阵肽结合途径的完整表征将通过直接模拟蛋白质-蛋白质缔合来实现，结合反应途径算法的应用，探索蛋白质二聚化和原纤维伸长。去发现那些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研究，涉及粗粒度的模型，多肽。这是必要的，因为所需的时间长得令人望而却步所有的原子模拟来检查大量的肽序列。使用非晶格和晶格模型（带侧链），Straub博士建议研究肽缔合的相行为、能量学和动力学。一进一步的目的是探索折叠中间体在促进聚合来简化的模型将被用来研究如何的细节，肽序列和初始条件影响原纤维形成。初步结果表明，原子模型和粗粒度模型都是有效的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，这是理解淀粉样疾病