Random Phase Detection for Accelerating Biomolecular NMR Experiments

用于加速生物分子 NMR 实验的随机相位检测

• 批准号: 8445739
• 负责人: JEFFREY C HOCH
• 金额: $ 22.99万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445739
• 关键词: A-factor (Streptomyces); Acceleration; Biological; Biological Process; Biomolecular Nuclear Magnetic Resonance; Blood; Cells; Code; Complex; Computer software; Crystallography; Data; Data Collection; Dependence; Detection; Dimensions; Discrimination; Disease; Entropy; Evolution; Face; Frequencies; Investigation; Joints; Measures; Methods; Metric; NMR Spectroscopy; Noise; Performance; Phase; Positioning Attribute; Process; Prolactin; Protein Dynamics; Protocols documentation; Records; Resolution; Sampling; Savings; Schedule; Scheme; Signal Transduction; Solutions; Source Code; Spectrum Analysis; Structure; Surveys; System; Technology; Time; Ubiquitin; computerized data processing; cost; drug discovery; flexibility; improved; molecular size; public health relevance; reconstruction; research study; three dimensional structure; time interval; tool; trend

DESCRIPTION (provided by applicant): Random Phase Detection for Acceleration of Biomolecular NMR Experiments High resolution NMR spectroscopy is a powerful tool for investigating biomolecular systems under solution conditions comparable to those encountered in the cell or blood. It is the only method capable of determining 3-dimensional structure in solution with atomic resolution. It also can be applied to highly dynamic or intrinsically disordered biomolecules that cannot be studied by x-ray crystallography. It is uniquely capable of determining both the extent and rate of structural fluctuations in solution, and there is a growing appreciation that understanding protein dynamics is essential for understanding their biological functions. It also a powerful method for probing biomolecular interactions, and has important applications in drug discovery. Although remarkable advances in technology have enabled the application of NMR to increasingly complex biomolecular systems, the full potential resolution afforded by high field magnets is generally not achieved along all the dimensions of multidimensional experiments due to practical limits on measuring time. By employing non- Fourier methods of spectrum analysis that do not require data to be sampled at uniform intervals, it is becoming possible to achieve much higher resolution in multidimensional NMR experiments using practical amounts of measuring time. A factor limiting the ability to shorten NMR experiments is the need to determine the sign of the frequency of signal components. Conventional approaches to determining the sign impose a factor of two sampling burden. We recently discovered that an approach in which the phase of the detected signal is randomly varied (random phase detection) enables determination of the sign of the frequency without imposing a factor of two sampling burden. The aim of this proposal is to explore the gains that can be achieved in reducing experiment time and/or improving resolution in multidimensional NMR experiments on biomolecules by combining nonuniform sampling in time with random phase detection. Further reductions in the time required to conduct multidimensional NMR experiments on biomolecules will render highly- dimensional experiments practical and extend applicability to systems that are fleetingly stable. Importantly, they will enable the full potentil resolution afforded by high-field magnets to be realized in the indirect dimensions of multidimensional experiments, extending the size and complexity of systems amenable to NMR investigation. Conversely, the reduced sampling requirements can be used to increase the sensitivity of multidimensional NMR, helping to facilitate the investigation of sparingly soluble o poorly abundant biomolecules.

描述（由申请人提供）：用于加速生物分子 NMR 实验的随机相检测高分辨率 NMR 波谱是在与细胞或血液中遇到的溶液条件相当的溶液条件下研究生物分子系统的强大工具。它是唯一能够以原子分辨率确定溶液中 3 维结构的方法。它还可以应用于无法通过 X 射线晶体学研究的高度动态或本质上无序的生物分子。它具有独特的能力，可以确定溶液中结构波动的程度和速率，并且人们越来越认识到了解蛋白质动力学对于了解其生物学功能至关重要。它也是探测生物分子相互作用的强大方法，并在药物发现中具有重要应用。尽管技术的显着进步使得核磁共振能够应用于日益复杂的生物分子系统，但由于测量时间的实际限制，高场磁体提供的全部潜在分辨率通常无法在多维实验的所有维度上实现。通过采用不需要以均匀间隔采样数据的非傅立叶光谱分析方法，可以使用实际的测量时间在多维核磁共振实验中实现更高的分辨率。限制缩短 NMR 实验能力的一个因素是需要确定信号分量的频率符号。确定符号的传统方法施加了两倍的采样负担。我们最近发现，一种随机改变检测到的信号的相位（随机相位检测）的方法可以确定频率的符号，而无需施加两倍的采样负担。该提案的目的是探索通过将时间不均匀采样与随机相位检测相结合，在生物分子多维 NMR 实验中减少实验时间和/或提高分辨率方面可以实现的收益。进一步减少对生物分子进行多维核磁共振实验所需的时间将使高维实验变得实用，并将适用性扩展到短暂稳定的系统。重要的是，它们将使高场磁体提供的全部电位分辨率在多维实验的间接维度中实现，从而扩展适合核磁共振研究的系统的尺寸和复杂性。相反，减少的采样要求可用于提高多维 NMR 的灵敏度，有助于促进难溶或丰度较差的生物分子的研究。