Developing Powder Crystallography for Molecules using NMR Parameters and Computations

核磁共振（NMR）实验在科学上广泛应用于阐明化学结构和动力学的许多方面。近年来，核磁共振实验已应用于固态有机分子，以进行晶体结构的细化、选择、验证和测定。在上述任务中，将定期将NMR数据与基于输入结构生成的计算输出进行比较。广义地说，这个过程被称为“核磁共振晶体学”（NMR- x）。该研究计划旨在改进当前协议的几个方面，并提出更多的创新，旨在提高核磁共振- x的准确性、效率和鲁棒性。我们未来五年研究计划的三个重点领域总结如下。1. 我们将提高结晶分子有机物计算核磁共振参数的准确性，同时在效率上做出最小的牺牲。目前最先进的核磁共振- x计算主要依赖于伪势来描述核心电子，平面波来描述价电子，并使用周期性边界条件来复制晶格的平移对称性。这种方法在计算核磁共振参数时相当准确，但有几个基本的限制。例如，执行包含精确电子交换的计算是非常低效的。这在目前的NMR-X方法中造成了依赖系统的“盲点”，必须加以纠正。该研究项目将开发一种局部嵌入方法，该方法将为更大范围的有机分子产生比目前更精确的核磁共振参数。2. 该研究计划将产生更强大的核磁共振- x指标。从本质上讲，指标是NMR-X社区的“统治者”，通过它可以建立提议的候选结构（或其他结构表征任务）的质量，我们的论点是，当前的指标并不健壮，因为它们可能导致结构质量的冲突估计。目前有几种核素（如1H、13C、15N、17O）和几种核磁共振参数（如化学位移）以某种形式存在度量。我们将首先为结构已知的化学体系建立可靠的核磁共振参数和核磁共振信号数据数据库，从而生成更稳健的指标。然后，我们将扩展当前的度量以包括温度效应，并随后考虑度量本身的替代数学结构。3. 通过将更精确的核磁共振参数计算和强大的核磁共振- x指标相结合，我们将开发核磁共振- x软件，可用于细化使用衍射方法确定的化学结构，重点是低分辨率的晶体结构。该研究项目将在制药行业取得有意义的成果。进一步的应用领域包括抗菌剂和共晶材料。

Nuclear magnetic resonance (NMR) experiments are widely used in science to elucidate many aspects of chemical structure and dynamics. Recently, NMR experiments have been applied to organic molecules in the solid state to perform crystal structure refinements, selections, verifications, and determinations. In the above tasks, the NMR data are regularly compared against computational outputs generated based on an input structure. Broadly speaking, this process is known as `NMR crystallography' (NMR-X). This research program seeks to improve several aspects of current protocols and proposes additional innovations with the aim of enhancing the accuracy, efficiency, and robustness of NMR-X. The three focus areas of our research program over the next five years are summarized below. 1. We will improve the accuracy of calculated NMR parameters for crystalline molecular organics while making minimal sacrifices in efficiency. Current state-of-the-art NMR-X computations rely largely on pseudopotentials to describe core electrons, planewaves to describe valence electrons, and use periodic boundary conditions to replicate the translational symmetry of the crystal lattice. This approach is fairly accurate when calculating NMR parameters yet has several fundamental limitations. For example, performing calculations that include exact electron exchange are highly inefficient. This creates system-dependent `blind spots' in present NMR-X approaches, which must be rectified. This research program will develop a local embedding approach that will produce more accurate NMR parameters for a larger set of organic molecules than is currently the case. 2. This research program will generate more robust NMR-X metrics. Essentially, metrics are the `rulers' by which those in the NMR-X community establish the quality of a proposed candidate structure (or other structure characterization task), and it is our contention that current metrics are not robust as they can lead to conflicting estimates of structure quality. Metrics currently exist in some form for several nuclides (e.g., 1H, 13C, 15N, 17O) and several NMR parameters (e.g., chemical shifts). We will generate more robust metrics by first establishing a database of reliable NMR parameters and NMR signal data for chemical systems whose structures are well known. We will then extend current metrics to include temperature effects and subsequently consider alternative mathematical structures for the metrics themselves. 3. By pairing the advances realized from access to more accurate NMR parameter computations and robust NMR-X metrics, we will develop NMR-X software that can be used to refine chemical structures determined using diffraction methods, with a focus on poorly resolved crystal structures. This research program will achieve meaningful results with impact in the pharmaceutical industry. Further application areas include antimicrobials and co-crystalline materials.