Magnetic Relaxation Dispersion

描述（由申请人提供）：核自旋-晶格弛豫速率常数的磁场依赖性，也称为磁弛豫色散（MRD），报告了由分子内和分子间运动产生的波动的功率密度作为核拉莫尔频率的函数，核拉莫尔频率可以在5 kHz到500 MHz之间变化，持续1小时。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1 ps阶的时间尺度。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，以及改变核自旋弛豫的因素（如MRI中使用的弛豫剂）提供了有力的方法。本实验室装配了独特的MRD测量仪器。我们建议：基于旋转固定蛋白质的MRD数据来表征蛋白质内部捕获水分子的动力学；定义膜结合蛋白在膜模型系统中控制水自旋晶格弛豫中的作用；将自旋分数子弛豫理论扩展到四极自旋、氘和氮-14的情况，以测试该理论的普遍性及其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水的高频运动；确定金属螯合物和有机自由基与旋转固定蛋白结合的最大水质子弛弛性条件，这对于理解靶向MRI造影剂如何起作用至关重要；测量10 kHz至500 MHz切除组织系统的精确松弛色散曲线，提供完整的数据集，以便与临床环境中积累的更多分散实验进行比较；测量模型组织基质中常见代谢物的31P和13C MRD谱，以在大范围内了解松弛机制；测量DNA作为模型刚性线性系统的MRD剖面并测试自旋分数子弛豫理论；通过直接检测蛋白质自旋来测量蛋白质中特定分子内载体的MRD谱；并使用碳酸酐酶II和synaptotagmin I的C2A结构域中的锌和钙金属位点与氮氧化物标记的半胱氨酸突变体结合来测量这些特定定义的分子内载体的完整MRD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再分配，或者结构干扰如何通过结构传播，作为功能的可能组成部分。这项工作在临床磁成像的背景下有直接的应用，无论是从现有的方法中提取额外的信息，还是开发新的靶向造影剂。

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.