Random Phase Detection for Accelerating Biomolecular NMR Experiments

描述(申请人提供)：随机相位检测加速生物分子核磁共振实验高分辨率核磁共振谱是在溶液条件下研究生物分子系统的强大工具，可与在细胞或血液中遇到的情况相媲美。这是唯一一种能够用原子分辨率确定溶液中三维结构的方法。它还可以应用于X射线结晶学无法研究的高动态或内在无序的生物分子。它是唯一能够确定溶液中结构波动的程度和速度的方法，人们越来越认识到，了解蛋白质动力学对于了解它们的生物学功能是必不可少的。它也是一种探测生物分子相互作用的有效方法，在药物发现中有重要的应用。尽管技术的显著进步使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不能在多维实验的所有维度上实现。通过使用不需要以均匀间隔采样数据的非傅立叶光谱分析方法，在使用实际测量时间的多维核磁共振实验中实现更高的分辨率是可能的。限制缩短核磁共振实验能力的一个因素是需要确定信号分量频率的符号。确定符号的传统方法施加了两个抽样负担的系数。我们最近发现，一种检测信号的相位随机变化的方法(随机相位检测)能够确定频率的符号，而不会施加两倍的采样负担。该方案的目的是探索在生物分子的多维核磁共振实验中，通过将时间非均匀采样与随机相位检测相结合，在缩短实验时间和/或提高分辨率方面所能获得的收益。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，并将适用范围扩大到短暂稳定的系统。重要的是，它们将使高场磁铁提供的全部潜在分辨率能够在多维实验的间接维度实现，扩大了可用于核磁共振研究的系统的规模和复杂性。相反，减少的采样要求可以用来提高多维核磁共振的灵敏度，有助于促进对稀有可溶或缺乏丰度的生物分子的研究。

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.