Probing the Principles Governing Protein Aggregation

探索蛋白质聚集的原理

基本信息

批准号：
7161783
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 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7161783
关键词：
Address Alzheimer&apos s Disease Amino Acids Amyloid Amyloid Proteins Amyloid beta-Protein Amyloidosis Area Behavior Bioinformatics Cereals Characteristics Charge Chemicals Collaborations Complex Computing Methodologies Condition Development Dimerization Disease Drug Formulations Electrostatics Elements Equilibrium Event Goals Housing Human Investigation 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 Public Health Range Rate Rattus Research Research Personnel Role Side Simulate Site Son Structure Temperature Testing Thermodynamics Time Urea Variant Vertebral column Work amyloid formation base computer studies dimer islet amyloid polypeptide molecular dynamics monomer mutant neurotoxicity novel oxidation peptide A polypeptide protein aggregation protein folding response simulation

项目摘要

DESCRIPTION (provided by applicant): This proposal is a request to continue highly productive research elucidating the fundamental principles underlying amyloid protein association and aggregation, linked to Alzheimer's Disease and other neurodegenerative disorders. The long-term goal is the formulation of the fundamental principles of polypeptide association and fibril formation, key to our understanding of amyloid disease. As a result of evidence suggesting that soluble low molecular weight (LMW) aggregates of amyloidogenic proteins are the primary cause of neurotoxicity, it has become urgent to understand the molecular mechanisms of formation of LMW oligomers. It is also necessary to explore the nature of external conditions, including pH, denaturant, and temperature that can drive conformational fluctuations in monomeric peptides making them prone to aggregation. 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 Amyloid beta-peptides, linked to Alzheimer's Disease, and human amylin, whose aggregation is implicated in type II diabetes. The effort has four specific aims: (1) Employ all-atom molecular dynamics simulations to probe the effects of sequence variations in the aggregation of Amyloid beta-peptides. These studies will map the assembly pathways in these peptides and provide a molecular-level understanding of the variations in observed fibrillization rates among naturally occurring Amyloid beta-peptide mutants. (2) Explore the factors that contribute to the stability of oligomers of Amyloid beta-peptides, and the response of interacting Ap-peptides to the denaturant urea. (3) Complete computational studies on why human amylin aggregates, while amylin from rats does not. Comparison of results for Amyloid beta and amylin peptides will provide a conceptual framework for understanding sequence and environmental effects on association of peptides and proteins. (4) Discover the general principles of polypeptide association. Detailed molecular dynamics simulations will be supplemented with coarse-grained off-lattice models of polypeptides. Employing such 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 this productive research collaboration has shown that a blend of atomically detailed simulations and studies of coarse-grained models is necessary to fully explore the complex problem of protein aggregation and amyloid formation. Relevance to Public Health. The proposed investigations will advance the study of the aggregation and reorganization of the amyloid p-peptide, implicated in Alzheimer's Disease, and other neurodegenerative disorders, as well as elucidate the factors that influence the formation of amylin polypeptide aggregates, implicated in type II diabetes.

描述（由申请人提供）：该提案是一项要求，旨在继续高度生产性研究，阐明淀粉样蛋白蛋白关联和聚集的基本原理，与阿尔茨海默氏病和其他神经退行性疾病有关。长期目标是制定多肽关联和原纤维形成的基本原理，这是我们对淀粉样蛋白疾病的理解的关键。由于证据表明淀粉样蛋白的可溶性低分子量（LMW）聚集体是神经毒性的主要原因，因此迫切需要了解LMW低聚物形成的分子机制已变得迫切。还必须探索外部条件的性质，包括pH，变性剂和温度，以驱动单体肽中的构象波动，从而使它们容易聚集。提出了一种多方面的方法，其中包括开发和使用新型计算方法来探测与阿尔茨海默氏病有关的淀粉样蛋白β-肽中低聚物形成的早期事件，以及与人类氨基疾病有关的，其聚集与II型糖尿病有关。这项工作具有四个特定的目的：（1）采用全原子分子动力学模拟来探测序列变化在淀粉样蛋白β-肽聚集中的影响。这些研究将绘制这些肽中的组装途径，并对天然存在的淀粉样蛋白β-肽突变体中观察到的纤维化速率变化提供分子级的理解。（2）探索淀粉样β-肽低聚物的稳定性的因素，以及相互作用的AP肽对变性尿素的反应。（3）完整的计算研究，说明为什么人淀粉蛋白聚集体，而来自大鼠的淀粉蛋白却没有。比较淀粉样蛋白β和淀粉蛋白肽的结果将提供一个概念框架，以了解序列和环境对肽和蛋白质缔合的影响。（4）发现多肽关联的一般原理。详细的分子动力学模拟将补充多肽的粗粒外晶格模型。将使用具有逼真的相互作用势的此类模型明确包括序列信息，肽关联的相行为，能量和动力学。这种生产性研究合作的过去工作表明，对于充分探索蛋白质聚集和淀粉样蛋白形成的复杂问题，必不可少的原子详细仿真和研究的研究。与公共卫生有关。提出的研究将进一步研究淀粉样蛋白P肽的聚集和重组，与阿尔茨海默氏病有关，以及其他神经退行性疾病，以及阐明影响淀粉蛋白酶多肽聚集物的因素，与II型糖尿病相关。