Developing Powder Crystallography for Molecules using NMR Parameters and Computations

核磁共振实验在科学上被广泛用于阐明化学结构和动力学的许多方面。最近，核磁共振实验已被应用于固态有机分子的晶体结构精炼、选择、验证和测定。在上述任务中，定期将核磁共振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‘核磁共振结晶学’(核磁共振-X)。这项研究计划寻求改进当前协议的几个方面，并提出额外的创新，目的是提高核磁共振-X的准确性、效率和稳健性。我们未来五年研究计划的三个重点领域概述如下。1.在以最小的效率为代价的前提下，提高晶体分子有机物核磁共振参数的计算精度。目前最先进的核磁共振-X计算在很大程度上依赖于赝势来描述核心电子，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是相当准确的，但有几个基本的限制。例如，执行包含精确电子交换的计算效率非常低。这在目前的核磁共振-X方法中造成了依赖于系统的“盲点”，必须加以纠正。这项研究计划将开发一种局部嵌入方法，该方法将为更多的有机分子产生比目前情况更准确的核磁共振参数。2.这项研究计划将产生更稳健的核磁共振-X指标。从本质上讲，度量是核磁共振-X社区中的那些人用来确定所提议的候选结构(或其他结构表征任务)的质量的‘尺子’，我们的论点是，当前的度量并不稳健，因为它们可能导致对结构质量的相互矛盾的估计。目前，对于几个核素(例如，1H、13C、15N、17O)和几个核磁共振参数(例如，化学位移)，存在某种形式的度量。我们将通过首先建立一个可靠的核磁共振参数和核磁共振信号数据的数据库，为结构众所周知的化学体系生成更稳健的指标。然后，我们将扩展当前的指标以包括温度影响，并随后考虑指标本身的替代数学结构。3.通过将获得更准确的核磁共振参数计算所实现的进步与强大的核磁共振-X度量相结合，我们将开发可用于精炼使用衍射法确定的化学结构的核磁共振-X软件，重点是分辨率较差的晶体结构。这一研究项目将取得有意义的成果，在制药行业产生影响。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.