Fast Kinetic Studies of Protein Folding and Function

蛋白质折叠和功能的快速动力学研究

基本信息

  • 批准号:
    7270641
  • 负责人:
  • 金额:
    $ 31.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-09-01 至 2009-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This project applies techniques for fast time-resolved magnetic circular dichroism (TRMCD), natural circular dichroism (TRCD, and ordinary absorption spectroscopies to the study of function in heme proteins and folding in heme proteins and small peptides. The novel optical methods employed use near-null ellipsometry and polarimetry to study rapid kinetic processes (nanosecond to seconds) in biomolecules that contain magneto-optically active chromophores, such as heme and the aromatic amino acids, and naturally chiral chromophores, such as the amide groups of proteins and peptides. These techniques will be used to identify and study the earliest (submillisecond) events in the folding reactions of heme proteins such as cytochrome c. A major goal is the determination of a parameter that is fundamental to understanding the nature of protein folding: the speed with which the different unfolded conformations interconvert with one another. If this is slow compared to folding itself, then understanding protein folding will require more complicated theories (e.g., energy landscape) than the transition state theory used for typical chemical reactions. Such understanding may ultimately prove helpful in developing therapies for the many diseases associated with protein misfolding, such as cystic fibrosis, type 2 diabetes, and Alzheimer's, Parkinson's, and Creutzfeldt- Jakob disease. A major goal of the functional studies is to understand how the four subunits that make up the hemoglobin molecule cooperate with each other to transport oxygen more efficiently. A recent hypothesis about this cooperativity (Ackers symmetry rule), based originally on thermodynamic measurements, is tested by kinetic measurements in this project. A novel model for hemoglobin allostery, emerging from this linkage of thermodynamics and kinetics, holds promise for simplifying and systematizing our understanding of hemoglobin's dynamics and its control in the body by allosteric effectors such as organic phosphates. In addition, TRMCD studies of the aromatic amino acid residue tryptophan [337, positioned at a site critical for cooperativity, are intended to further clarify how hemoglobin's subunits work together as an efficient "molecular machine" for transporting oxygen from the lungs to the tissues.
项目描述(由申请人提供):本项目应用快速时间分辨磁圆二色(TRMCD)、自然圆二色(TRCD)和普通吸收光谱技术研究血红素蛋白的功能和血红素蛋白和小肽的折叠。新的光学方法采用近零椭偏和偏振法来研究生物分子的快速动力学过程(纳秒到秒),这些生物分子含有磁光活性发色团,如血红素和芳香氨基酸,以及天然手性发色团,如蛋白质和肽的酰胺基团。这些技术将用于识别和研究血红素蛋白(如细胞色素c)折叠反应中的最早(亚毫秒)事件。一个主要目标是确定一个参数,这是理解蛋白质折叠本质的基础:不同的未展开构象相互转换的速度。如果这与折叠本身相比是缓慢的,那么理解蛋白质折叠将需要比用于典型化学反应的过渡态理论更复杂的理论(例如,能量景观)。这样的理解最终可能有助于开发与蛋白质错误折叠相关的许多疾病的治疗方法,如囊性纤维化、2型糖尿病、阿尔茨海默病、帕金森病和克雅氏病。功能研究的一个主要目标是了解组成血红蛋白分子的四个亚基如何相互合作以更有效地运输氧气。最近关于这种协同性的假设(Ackers对称规则),最初基于热力学测量,在本项目中通过动力学测量进行了测试。一个新的血红蛋白变构模型,从热力学和动力学的联系中出现,有望简化和系统化我们对血红蛋白动力学及其在体内由变构效应物(如有机磷酸盐)控制的理解。此外,TRMCD对位于协同作用关键位点的芳香氨基酸残基色氨酸[337]的研究,旨在进一步阐明血红蛋白亚基如何作为一个有效的“分子机器”共同工作,将氧气从肺部运输到组织。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Early events, kinetic intermediates and the mechanism of protein folding in cytochrome C.
Nanosecond time-resolved polarization spectroscopies: tools for probing protein reaction mechanisms.
  • DOI:
    10.1016/j.ymeth.2010.04.015
  • 发表时间:
    2010-09
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Chen, Eefei;Goldbeck, Robert A.;Kliger, David S.
  • 通讯作者:
    Kliger, David S.
Probing kinetic mechanisms of protein function and folding with time-resolved natural and magnetic chiroptical spectroscopies.
利用时间分辨自然和磁手性光谱探测蛋白质功能和折叠的动力学机制。
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DAVID S. KLIGER其他文献

DAVID S. KLIGER的其他文献

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{{ truncateString('DAVID S. KLIGER', 18)}}的其他基金

Circular Dichroism Spectropolarimeter
圆二色性分光偏振计
  • 批准号:
    8639931
  • 财政年份:
    2014
  • 资助金额:
    $ 31.42万
  • 项目类别:
Fast Kinetic Studies of Protein Folding and Function
蛋白质折叠和功能的快速动力学研究
  • 批准号:
    7098013
  • 财政年份:
    2004
  • 资助金额:
    $ 31.42万
  • 项目类别:
Fast Kinetic Studies of Protein Folding and Function
蛋白质折叠和功能的快速动力学研究
  • 批准号:
    6874802
  • 财政年份:
    2004
  • 资助金额:
    $ 31.42万
  • 项目类别:
Fast Kinetic Studies of Protein Folding and Function
蛋白质折叠和功能的快速动力学研究
  • 批准号:
    6945191
  • 财政年份:
    2004
  • 资助金额:
    $ 31.42万
  • 项目类别:
SMALL INSTRUMENTATION GRANT
小型仪器补助金
  • 批准号:
    3524856
  • 财政年份:
    1991
  • 资助金额:
    $ 31.42万
  • 项目类别:
TIME-RESOLVED MAGNETIC CIRCULAR DICHROISM
时间分辨磁圆二色性
  • 批准号:
    6519266
  • 财政年份:
    1987
  • 资助金额:
    $ 31.42万
  • 项目类别:
TIME-RESOLVED MAGNETIC CIRCULAR DICHROISM
时间分辨磁圆二色性
  • 批准号:
    2900657
  • 财政年份:
    1987
  • 资助金额:
    $ 31.42万
  • 项目类别:
TIME-RESOLVED MAGNETIC CIRCULAR DICHROISM
时间分辨磁圆二色性
  • 批准号:
    6635957
  • 财政年份:
    1987
  • 资助金额:
    $ 31.42万
  • 项目类别:
TIME-RESOLVED MAGNETIC CIRCULAR DICHROISM
时间分辨磁圆二色性
  • 批准号:
    6127433
  • 财政年份:
    1987
  • 资助金额:
    $ 31.42万
  • 项目类别:
TIME-RESOLVED MAGNETIC CIRCULAR DICHROISM
时间分辨磁圆二色性
  • 批准号:
    6385684
  • 财政年份:
    1987
  • 资助金额:
    $ 31.42万
  • 项目类别:
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