Deuteron Nuclear Magnetic Resonance Studies of Oriented Proteins and Model Compou

描述（由申请人提供）：这是一项将固态氘核磁共振（NMR）技术应用于模型化合物和小蛋白质取向体系中分子动力学定量研究的提案。这包括开发和测试新的脉冲序列，以提高特定地点的光谱分辨率，设计现实的，新的运动模型，解释相关运动，并提供良好的记录，易于使用的软件，用于分析一般的生物分子运动。尽管大多数具有生物学意义的运动（例如，酶催化，分子识别等）发生在室温附近的水溶液中，但目前对固态核磁共振方法研究生物动力学的浓厚兴趣有令人信服的理由。其中一个动机是，大型生物分子的局部内部运动肯定与它们的功能有关，但由于整个分子整体缓慢翻滚的干扰，很难通过溶液态核磁共振进行研究。第二个动机是，准确确定不同运动过程的活化能，可以通过折叠蛋白质的复杂势能格局提供有关最小能量途径的有用信息，通常需要在水溶液无法达到的广泛温度范围内进行测量。第三个动机是，与定向膜中蛋白质和小分子运动相关的运动时间尺度通常太长，无法通过完整的分子动力学模拟进行研究，但很容易通过通常用于描述固体运动的适当适应模型进行模拟。计算机技术的最新进展允许使用复杂的运动模型来模拟核磁共振线形状和自旋弛豫行为，而仅仅在几年前，这些模型还被认为是计算成本太高的。这种模型的一个问题是它们有大量可调参数：很少有研究报告以系统的方式评估给定模型中的哪些参数可以从哪种实验核磁共振数据中可靠地确定。第二个问题是，设计一个复杂的模型需要设计者非常熟悉求解大型耦合微分方程集的复杂数学过程。本提案中描述的图形用户界面通过为用户提供先进的统计工具来评估参数可靠性，并允许用户在任何可能的情况下以化学直观的方式指定运动轨迹和速率，从而解决了这两个问题。因此，它将极大地促进非固态核磁共振专家利用这一重要技术的能力。

DESCRIPTION (provided by applicant): This is a proposal to adapt techniques developed for solid state deuteron nuclear magnetic resonance (NMR) to quantitative investigations of molecular dynamics in oriented systems of model compounds and small proteins. This includes developing and testing new pulse sequences to improve site-specific spectral resolution, designing realistic, new motional models that account for correlated motions, and providing well documented, easy to use software for analysis of biomolecular motion in general. Even though most biologically significant motions (e.g., enzyme catalysis, molecular recognition, etc.) occur near room temperature in aqueous solutions, there are compelling reasons for the current intense interest in solid state NMR methodology for studying biodynamics. One motivation is the fact that local, internal motions in large biomolecules are surely relevant to their function, but are difficult to study by solution state NMR due to interference from slow overall tumbling of the whole molecule. A second motivation is that accurate determination of the activation energies for different motional processes, which can provide useful information about minimum energy pathways through the complex potential energy landscape of a folding protein, typically requires measurements over a wide range of temperatures not accessible with aqueous solutions. A third motivation is that the motional time scales relevant for motion of proteins and small molecules in oriented membranes are often too long to be investigated by full molecular dynamic simulations, but are readily accessible to simulation suitably adapted models commonly used to describe motion in solids. Recent advances in computer technology permit simulations of NMR line shapes and spin relaxation behavior to be carried out using complex motional models that only a few years ago would have been deemed too computationally expensive. One problem with such models is their large number of adjustable parameters: few studies have been reported that assess in a systematic manner which parameters in a given model can be determined reliably from what kinds of experimental NMR data. A second problem is that designing a complex model requires significant familiarity on the part of the designer with intricate mathematical procedures for solving large sets of coupled differential equations. The graphical user interface described in this proposal addresses both these problems by providing users with advanced statistical tools for assessing parameter reliability, and allowing the user wherever possible to specify motional trajectories and rates in chemically intuitive terms. Thus, it will greatly facilitate the ability of non-specialists in solid state NMR to exploit this important technique.