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

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.