Project Summary / Abstract This proposal requests support for the acquisition of a new X-ray diffractometer to be housed in the Chemistry Department at Johns Hopkins University (JHU). The requested instrument is a Rigaku XtaLAB Synergy-R system equipped with a high-flux rotating anode X-ray source and a Hybrid Photon Counting detector. This instrument will dramatically advance the capabilities in fundamental research of 19 Major and Minor Users identified in the proposal, involving investigators from chemistry, biophysics, materials science, and chemical and biomolecular engineering. There have been significant advancements in X-ray diffractometer technology since the prior acquisition (2012) of the current diffractometer housed in Chemistry at JHU, and these advances allow for a major leap forward in the characterization of challenging crystalline materials. Such materials are: (i) compounds that do not crystallize well and/or grow with only very small crystal dimensions (e.g. 10-40 µm), (ii) high value chemical target molecules (e.g., intermediate species, novel metal-organic frameworks, supramolecular assemblies) that have limiting diffraction power due to poor long-range order, and/or contain large amounts of solvent inclusion, and (iii) proteins with relatively long unit cell dimensions (> 150 Å). These materials would be extremely difficult, or impossible, to characterize with the current instrumentation at JHU. The proposed instrument will transform the NIH-funded research of Major Users Goldberg, Karlin, and Garcia-Bosch by providing molecular structures of compounds that are meta-stable and can only be isolated in crystals of very small dimensions and/or are weakly diffracting; and of Major User Huang by characterizing metalloproteins for catalytic functions. The delineation of structural, host-guest interactions in framework materials (e.g. metal-organic and covalent organic frameworks (MOFs, COFs)) is critical to the research of Major User Thoi, but the fragility, porosity, and small size of single crystals of these frameworks often makes structural characterization impossible. The proposed Rigaku XtaLAB Synergy- R diffractometer should overcome these barriers and enable the examination of host-guest relationships, single-crystal-to-single-crystal transformations, and snapshots of chemical mechanism in MOF/COF materials. The power of the proposed diffractometer will also allow Major User García-Moreno to examine structure-energy relationships in proteins, especially with regards to pH sensitivity. Such studies are important in cancer biology, as one of the hallmarks of cancerous solid tumors is dysregulation of pH, and the fundamental structural knowledge to be gained can be harnessed to increase the specificity of protein therapeutics. Overall, the acquisition of the proposed instrument will greatly enhance the research of Major and Minor users by providing the ability to obtain detailed structural information on small molecules and ...