Probing the Principles Governing Protein Aggregation

探索蛋白质聚集的原理

基本信息

批准号：
7529008
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
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529008
关键词：
Address Alzheimer&apos s Disease Amino Acids Amyloidosis Area Behavior Bioinformatics Cereals Characteristics Charge Chemicals Collaborations Complex Computing Methodologies 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 Pathway interactions Peptides Phase Protein Dynamics Proteins 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

项目摘要

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.

该提案是一项要求继续旨在阐明基本原则的高度生产研究的要求淀粉样肽的关联和聚集。已知序列蛋白的聚集与阿尔茨海默氏症（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）淀粉样蛋白的聚集体是神经毒性的主要原因，有迫切了解分子 LMW低聚物形成的机理。另外，有必要阐明包括pH，包括pH的外部条件的性质变性剂和温度，可以驱动单体肽中构象波动，使它们容易到聚合。拟议的努力的长期目标是制定基本原理对多肽关联和原纤维形成。为了实现这一目标，提出了一种多面方法，其中包括开发和使用新型计算探测导致寡聚形成的早期事件的方法（与AD相关的3肽和人淀粉素聚集与II型糖尿病有关。这项工作由针对四个特定目标的项目组成：（1）分子动力学模拟将用于探测序列变化在A0肽聚集中的影响。这些研究将导致这些肽中的组装途径图，并提供分子水平的理解。天然围绕AP肽突变体观察到的纤维化速率的变化。（2）剖析因素有助于3肽的低聚物的稳定性，相互作用的AP肽对变性剂的反应，例如尿素和将探索盐酸鸟嘌呤。（3）计算研究以了解为什么人淀粉蛋白聚集体，而来自大鼠的淀粉素不会完成。通过比较AP和AMYLIN肽的结果，这是一个概念框架将开发了解肽和蛋白质关联的序列和环境反馈。（4）发现多肽关联的一般原理，详细的分子型模拟将补充研究涉及多肽的粗粒外晶格模型。具有现实互动潜力的工作模型明确包括序列信息，将检查肽关联的相行为，能量和动力学。生产研究合作的过去工作表明，将原子详细的模拟和研究结合在一起粗粒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肽级的肽聚集有了概念性的理解，这对于淀粉样蛋白的理解至关重要疾病。