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Early Events in Protein Folding

蛋白质折叠的早期事件

基本信息

批准号：
7870678
负责人：
RICHARD BRIAN DYER
金额：
$ 32.68万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7870678
关键词：
Address Amino Acid Sequence Appendix Authorization documentation Biological Biological Models Budgets California Characteristics Child Cities Class Classification Clinical Trials Complex Coupled Data Dependence Depth Development Development Plans Diffusion Disclosure Engineering Escherichia coli Event Face Fluorescence Foundations Grant Helix (Snails)Human Resources Instruction Isotopes Kinetics Laboratories Lasers Last Name Length Letters Literature Manuscripts Methods Microscopic Minority Modeling Molecular Monitor Names Numbers Peptides Phase Positioning Attribute Postdoctoral Fellow Principal Investigator Printing Process Progress Reports Proteins Publications Range Rate Reaction Registries Relaxation Relaxation Techniques Research Research Design Research Project Grants Resources Role Safety Shapes Spectrum Analysis Structure System Techniques Tertiary Protein Structure Testing Time Universities Vertebrates Woman Work analog apomyoglobin base beta pleated sheet cold shock protein ear helix homeodomain human subject i(19)molecular dynamics novel strategies performance site programs protein E protein folding temperature jump

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to characterize the dynamics and molecular mechanisms of protein folding. We seek to determine the characteristic rates and underlying molecular mechanisms of the fundamental processes, including chain collapse, secondary structure formation, and formation of specific tertiary interactions. The basic questions we plan to address include: What are the fundamental dynamics, transition state structures and folding mechanisms of ultrafast folding proteins? Can ultrafast folding proteins be made to fold without crossing a free energy barrier (downhill folding)? What is the role of residual structure in the denatured state, and does such structure speed folding? Do peptide models and ultrafast folding subdomains exhibit the same folding behavior in the context of the full protein? These questions are the subject of intense scrutiny and debate in the current protein folding literature. We propose a close interaction between experiment and simulation to answer these questions. We have designed experimental approaches to quantitatively test the predictions of MD simulations of ultrafast folding proteins. In turn, we expect MD simulations to motivate new experiments, or help in the interpretation of experimental observables. We expect such a close interplay between experiment and theory to greatly benefit both, and ultimately improve our understanding of how proteins fold. PUBLIC HEALTH RELEVANCE Understanding how a protein folds to its native, biologically active structure continues to be a central problem of modern biology, with important practical consequences for rational protein design, protein structure prediction and folding related disease states. The aggregation and deposition of misfolded proteins, sometimes the consequence of a single point mutation, is a common feature of neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, and motor neuron disease. The proposed work will provide new understanding of how proteins fold, and what goes wrong when they misfold and cause disease.

描述（由申请人提供）：本提案的总体目标是表征蛋白质折叠的动力学和分子机制。我们试图确定的基本过程，包括链崩溃，二级结构的形成，并形成特定的三级相互作用的特征速率和潜在的分子机制。我们计划解决的基本问题包括：超快折叠蛋白质的基本动力学，过渡态结构和折叠机制是什么？超快折叠蛋白质是否可以在不跨越自由能势垒的情况下折叠（下坡折叠）？在变性状态下，残余结构的作用是什么？这种结构会加速折叠吗？肽模型和超快折叠亚结构域在完整蛋白质的背景下表现出相同的折叠行为吗？这些问题是当前蛋白质折叠文献中激烈审查和辩论的主题。我们建议实验和模拟之间的密切互动来回答这些问题。我们设计了实验方法来定量测试超快折叠蛋白质的MD模拟的预测。反过来，我们希望MD模拟能够激发新的实验，或者帮助解释实验观测值。我们希望实验和理论之间的这种密切相互作用对双方都有很大的好处，并最终提高我们对蛋白质折叠方式的理解。了解蛋白质如何折叠成其天然的生物活性结构仍然是现代生物学的中心问题，对于合理的蛋白质设计，蛋白质结构预测和折叠相关的疾病状态具有重要的实际意义。错误折叠蛋白质的聚集和沉积，有时是单点突变的结果，是神经变性疾病的常见特征，如阿尔茨海默病、帕金森病、朊病毒病、亨廷顿病和运动神经元病。这项工作将为蛋白质如何折叠以及当它们错误折叠并导致疾病时出现什么问题提供新的理解。