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Magnetic Relaxation Dispersion

磁弛豫色散

基本信息

批准号：
8073934
负责人：
Robert George Bryant
金额：
$ 29.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-06-01 至 2013-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The magnetic field dependence of the nuclear spin-lattice relaxation rate constant, also called the magnetic relaxation dispersion (MRD), reports the power density of fluctuations created by intra- and inter-molecular motions as a function of the nuclear Larmor frequency, which may be varied from 5 kHz to 500 MHz for 1H. The use of paramagnetic contributions to the nuclear relaxation extends the effective frequency range to 0.3 THz or time scales of order 1 ps. Combined with appropriate statistical theories, the MRD profiles provide a powerful method for studying molecular dynamics, protein dynamics in particular, and factors that modify nuclear spin relaxation such as relaxation agents used in MRI. This laboratory has assembled unique instrumentation for MRD measurements. We propose to: characterize the dynamics of internally trapped water molecules in proteins based on MRD data from rotationally immobilized proteins; define the role of membrane- bound proteins in controlling water spin-lattice relaxation in membrane model systems; extend the spin-fracton relaxation theory to the case of quadrupolar spins, deuterium and nitrogen-14, to test the generality of the theory and the implications for energy redistribution in proteins; measure the high frequency motions of water adjacent to specific paramagnetic centers in proteins; define the conditions for maximum water-proton relaxivity for metal chelate and organic radicals conjugated to rotationally immobilized proteins, which is important in understanding how targeted MRI contrast agents can work; measure accurate relaxation dispersion profiles for excised tissue systems from 10 kHz to 500 MHz to provide complete data sets for comparison with much more scattered experiments accumulated in a clinical setting; measure 31P and 13C MRD profiles for commonly observed metabolites in a model tissue matrix to provide an understanding of the relaxation mechanisms over a wide field range; measure the MRD profiles and test the spin-fracton relaxation theory for DNA as a model stiff linear system; measure the MRD profiles for specific intramolecular vectors in proteins using direct detection of protein spins; and use zinc and calcium metal sites in carbonic anhydrase II and the C2A domain of synaptotagmin I in combination with nitroxide labeled cysteine mutants to measure complete MRD profiles of these specifically defined intramolecular vectors. The results of these studies have direct bearing on how we understand energy redistribution in proteins or how structural disturbances propagate through the structure as a possible component of function. There are immediate applications of this work in the context of clinical magnetic imaging, both in extracting additional information from existing approaches and the development of new classes of targeted contrast agents. This project will use measurements of nuclear spin-lattice relaxation rate constants to deduce the nature of intra and inter-molecular motions in proteins that affect contrast in MRI and the information that may be obtained from in vivo magnetic resonance protocols. Included are studies targeted spin-relaxation or contrast agents for MRI that are fundamentally different in design and action from presently used soluble contrast agents. The molecular biophysical foundations of this work are important for understanding the functional role of protein dynamics.

描述(由申请人提供)：核自旋-晶格驰豫速率常数的磁场依赖性，也称为磁弛豫色散(MRD)，报告了分子内和分子间运动所产生的涨落的功率密度作为核Larmor频率的函数，对于1H，可能从5 kHz到500 MHz变化。利用顺磁对核弛豫的贡献将有效频率范围扩展到0.3太赫兹或1ps量级的时间尺度。结合适当的统计理论，MRD谱为研究分子动力学，特别是蛋白质动力学，以及改变核自旋松弛的因素，如磁共振成像中使用的弛豫剂，提供了一种强有力的方法。这个实验室组装了用于MRD测量的独特仪器。我们建议：基于旋转固定蛋白质的MRD数据来表征蛋白质中内部捕获的水分子的动力学；定义膜结合蛋白质在膜模型系统中控制水自旋-晶格驰豫的作用；将自旋分数弛豫理论扩展到四极自旋、氦和氮-14的情况，以测试理论的普适性和对蛋白质中能量再分配的影响；测量蛋白质中特定顺磁中心附近的水的高频运动；定义金属螯合物和有机自由基在旋转固定蛋白质上的最大水质子弛豫度的条件，这对于理解靶向磁共振造影剂如何工作很重要；测量从10 kHz到500 MHz的切除组织系统的准确弛豫色散分布，以提供完整的数据集，用于与在临床环境中积累的更分散的实验进行比较；测量模型组织基质中常见观察到的代谢物的31P和13C MRD分布，以在广泛的领域范围内提供对松弛机制的理解；测量作为模型刚性线性系统的DNA的自旋-分数松弛理论；使用直接检测蛋白质自旋，测量蛋白质中特定分子内载体的MRD分布；并使用碳酸氢酶II中的锌和钙金属位点以及突触素I的C2a结构域与氮氧化物标记的半胱氨酸突变体相结合来测量这些特定定义的分子内载体的完整MRD图谱。这些研究的结果直接关系到我们如何理解蛋白质中的能量重新分配，或者结构扰动如何作为功能的一个可能组成部分通过结构传播。这项工作在临床磁成像方面有直接的应用，既可以从现有的方法中提取额外的信息，也可以开发新的靶向造影剂。这个项目将使用核自旋-晶格驰豫速率常数的测量来推断蛋白质分子内和分子间运动的性质，这些运动影响磁共振成像中的对比度，以及可能从体内磁共振方案中获得的信息。包括针对MRI的自旋松弛或造影剂的研究，它们在设计和作用上与目前使用的可溶性造影剂有根本的不同。这项工作的分子生物物理基础对于理解蛋白质动力学的功能作用很重要。