Deuteron Nuclear Magnetic Resonance Studies of Oriented Proteins and Model Compou

定向蛋白质和模型化合物的氘核磁共振研究

• 批准号: 8089900
• 负责人: Robert L. Vold
• 金额: $ 33.25万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089900
• 关键词: Accounting; Address; Alaska; Alzheimer' s Disease; Amino Acids; Behavior; Binding Proteins; Biological Models; Catalysis; Chickens; Collaborations; Complex; Computer Analysis; Computer software; Computers; Coupled; Data; Drug Formulations; Environment; Enzymes; Equation; Familiarity; Goals; Investigation; Lead; Least-Squares Analysis; Measurement; Membrane; Methodology; Microscopic; Modeling; Molecular; Morphologic artifacts; Motion; Motivation; Neurodegenerative Disorders; Nuclear Magnetic Resonance; Parkinson Disease; Pathway interactions; Physiologic pulse; Plant Roots; Potential Energy; Procedures; Process; Proteins; Public Domains; Relaxation; Reporting; Resolution; Retinal Cone; Shapes; Side; Site; Solid; Solutions; Spin Labels; System; Techniques; Technology; Temperature; Testing; Time; To specify; Universities; Vertebral column; aqueous; base; design; deuteron; globular protein; graphical user interface; improved; interest; liquid crystal; macromolecule; magnetic field; molecular dynamics; molecular recognition; protein folding; quantum; research study; simulation; single bond; small molecule; solid state; solid state nuclear magnetic resonance; tool; villin

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. PUBLIC HEALTH RELEVANCE: Local motions in biologically active macromolecules are crucial for their function. Thus the detailed understanding of these motions, which can be gained using the proposed experiments and associated computer analysis, could significantly improve our understanding of the root causes of many neurodegenerative diseases such as Alzheimer's and Parkinson's, that result from abnormal microscopic dynamics.

描述（由申请人提供）：这是一项将固态氘核核磁共振（NMR）开发的技术应用于模型化合物和小蛋白质定向系统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位点的光谱分辨率，设计考虑相关运动的真实的新运动模型，以及提供有据可查且易于使用的软件来分析一般生物分子运动。 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，但目前人们对研究生物动力学的固态核磁共振方法有浓厚的兴趣，这是有令人信服的理由的。一个动机是，大生物分子中的局部内部运动肯定与其功能相关，但由于整个分子缓慢整体翻滚的干扰，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，这可以提供有关通过折叠蛋白的复杂势能景观的最小能量路径的有用信息，通常需要在水溶液无法达到的较宽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的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来研究，但可以很容易地模拟通常用于描述固体运动的适当适应的模型。 计算机技术的最新进展允许使用复杂的运动模型来模拟 NMR 线形状和自旋弛豫行为，而仅在几年前，这些模型还被认为计算成本太高。这种模型的一个问题是它们有大量的可调节参数：很少有研究报告能够以系统的方式评估给定模型中的哪些参数可以根据哪种实验核磁共振数据可靠地确定。第二个问题是，设计复杂模型需要设计者非常熟悉用于求解大量耦合微分方程组的复杂数学过程。该提案中描述的图形用户界面通过为用户提供用于评估参数可靠性的先进统计工具来解决这两个问题，并允许用户尽可能以化学直观的方式指定运动轨迹和速率。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。 公共卫生相关性：生物活性大分子的局部运动对其功能至关重要。因此，通过所提出的实验和相关的计算机分析可以获得对这些运动的详细理解，可以显着提高我们对许多神经退行性疾病（如阿尔茨海默氏症和帕金森氏症）根源的理解，这些疾病是由异常的微观动力学引起的。