Expanding the Scope of Powder X-ray Diffraction: Development and Application of Next-generation Methodology for Structure Determination

该研究项目的重点是开发和应用从粉末x射线衍射（XRD）数据中进行有机材料结构测定的新技术。自20世纪90年代初首次通过粉末XRD数据确定有机材料的结构以来，该领域的进步为获得不适合单晶XRD（最广泛使用的结构测定技术）研究的材料的结构理解（从而使性能和功能合理）提供了机会。特别是20世纪90年代初结构求解“直接空间策略”的提出和发展，改变了这一领域，目前已成为利用粉末XRD数据进行有机材料结构测定的标准方法。然而，为了扩大这一代技术的范围，从而推进这一领域的最新技术，探索从粉末XRD数据中进行有机材料结构测定的新的更强大的策略是必不可少的。在这方面，我们最近开始探索一个新的机会，通过结合其他技术的补充信息，特别是固态核磁共振数据和周期密度泛函理论（DFT-D）计算，增强粉末XRD数据的分析。该策略中包含的实验和计算方法的协同作用代表了一个实质上更强大的过程，我们相信这将使未来能够确定更复杂的晶体结构。博士项目的目标是充分开发和优化这种结合粉末XRD/固态NMR/DFT-D策略，作为从粉末XRD数据确定有机材料结构的下一代方法，优化的策略也将在项目中应用，以解决当前方法范围之外的一系列更复杂的结构问题。目标材料包括：(i)具有生物学意义的材料（多肽），（ii）金属有机框架（mof）， （iii）聚合物材料，以及（iv）具有重要药用价值的材料。在这些应用领域中，主要的重点将放在生物学上重要的多肽的结构确定上，重点放在三个不同的模型系统上。第一个系统是基于P2X受体中关键功能基序的结构，P2X受体是一个atp门控阳离子通道家族，在疼痛和炎症中发挥重要作用。第二个系统是具有生物活性的钙样肽（CALPs）多肽家族，这是一种短肽（含有8到12个氨基酸），对普遍存在的钙结合信使蛋白钙调蛋白（钙调节蛋白）具有明确的激动剂和拮抗剂活性。第三个系统主要研究形成α -螺旋结构的肽段，这是最常见的跨膜蛋白二级结构，被认为是未来粉末XRD研究膜蛋白结构的重要一步。这三种体系都代表了从粉末XRD数据中确定结构的挑战性问题，但我们相信它们是利用粉末XRD/固态NMR/DFT-D组合策略的现实目标，该策略将在本项目中开发和优化。当然，这些目标材料结构的成功确定将大大扩展粉末XRD的范围和范围，为未来更大的生物分子的研究打开机会。项目的结构将主要侧重于第一年的方法开发，第二年完成方法开发和启动应用，第三年侧重于新方法的应用，确保在项目的3.5年时间框架内完成大量新的和原始的研究。

The research project is focused on the development and application of new techniques for carrying out structure determination of organic materials from powder X-ray diffraction (XRD) data. Since the first structure determination of an organic material from powder XRD data in the early 1990s, advances in this field have opened up the opportunity to gain structural understanding (and hence to rationalize properties and function) of materials that are unsuitable for investigation by single-crystal XRD (the most widely-used technique for structure determination). In particular, the proposal and development of the "direct-space strategy" for structure solution in the early 1990s transformed this field, and is now the standard method for carrying out structure determination of organic materials from powder XRD data.However, to extend the scope of the present generation of techniques and hence to advance the current state-of-the-art in this field, it is essential to explore new and more powerful strategies for carrying out structure determination of organic materials from powder XRD data. In this regard, we have recently started to explore a new opportunity that enhances the analysis of powder XRD data by incorporating complementary information from other techniques, in particular solid-state NMR data and periodic density functional theory (DFT-D) calculations. The synergy of experimental and computational methods embodied within this strategy represents a substantially more powerful procedure, which we believe will enable crystal structures of significantly greater complexity to be determined in the future.The aim of the PhD project is to fully develop and optimize this combined powder XRD/solid-state NMR/DFT-D strategy as the next-generation approach for structure determination of organic materials from powder XRD data, and the optimized strategy will also be applied in the project to tackle a range of structural problems of greater complexity that are beyond the scope of current methods. Target materials include: (i) materials of biological interest (polypeptides), (ii) metal-organic frameworks (MOFs), (iii) polymeric materials, and (iv) pharmaceutically important materials.Within these fields of application, the major focus will be on structure determination of biologically important polypeptides, focusing on three distinct model systems. The first system is based on the structures of key functional motifs in P2X receptors, a family of ATP-gated cation channels that play important roles in pain and inflammation. The second system is the biologically active polypeptide family of calcium-like peptides (CALPs), which are short peptides (containing between 8 and 12 amino acids) with defined agonist and antagonist activity at the ubiquitous calcium-binding messenger protein calmodulin (calcium-modulated protein). The third system, which is identified as an important step towards the future development of powder XRD to study membrane protein structure, is focused on peptides that form alpha-helix structures, the most common membrane-spanning protein secondary structure. All three systems represent challenging problems for structure determination from powder XRD data, but we are confident that they are realistic targets for exploiting the combined powder XRD/solid-state NMR/DFT-D strategy that will be developed and optimized in this project. Certainly, successful structure determination of these target materials will significantly extend the range and scope of powder XRD, opening the opportunity for the study of larger biological molecules in the future.The project will be structured to focus primarily on method development in Year 1, completion of method development and initiation of applications in Year 2, and focus on applications of the new methodology in Year 3, ensuring completion of a significant amount of new and original research within the 3.5 year timeframe of the project.