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Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures Lisa M. Baker , Anthony Aimon , James B. Murray , Allan E. Surgenor , Natalia Matassova , Stephen D. Roughley , Patrick M. Collins , Tobias Krojer , Frank Von Delft , Roderick E. Hubbard Communications Chemistry 3 DOI: 10.1038/s42004-020-00367-0 Open Access Show Abstract ▼ Abstract: Fragment based methods are now widely used to identify starting points in drug discovery and generation of tools for chemical biology. A significant challenge is optimization of these weak binding fragments to hit and lead compounds. We have developed an approach where individual reaction mixtures of analogues of hits can be evaluated without purification of the product. Here, we describe experiments to optimise the processes and then assess such mixtures in the high throughput crystal structure determination facility, XChem. Diffraction data for crystals of the proteins Hsp90 and PDHK2 soaked individually with 83 crude reaction mixtures are analysed manually or with the automated XChem procedures. The results of structural analysis are compared with binding measurements from other biophysical techniques. This approach can transform early hit to lead optimisation and the lessons learnt from this study provide a protocol that can be used by the community.	Sep 2020
B21-High Throughput SAXS B23-Circular Dichroism	Revealing the complexity of ionic liquid–protein interactions through a multi-technique investigation Liem Bui-le , Coby J. Clarke , Andreas Brohl , Alex P. S. Brogan , James A. J. Arpino , Karen M. Polizzi , Jason P. Hallett Communications Chemistry 3 DOI: 10.1038/s42004-020-0302-5 Diamond Proposal Number(s): [19247, 21035] Open Access Show Abstract ▼ Abstract: Ionic liquids offer exciting possibilities for biocatalysis as solvent properties provide rare opportunities for customizable, energy-efficient bioprocessing. Unfortunately, proteins and enzymes are generally unstable in ionic liquids and several attempts have been made to explain why; however, a comprehensive understanding of the ionic liquid–protein interactions remains elusive. Here, we present an analytical framework (circular dichroism (CD), fluorescence, ultraviolet-visible (UV/Vis) and nuclear magnetic resonance (NMR) spectroscopies, and small-angle X-ray scattering (SAXS)) to probe the interactions, structure, and stability of a model protein (green fluorescent protein (GFP)) in a range (acetate, chloride, triflate) of pyrrolidinium and imidazolium salts. We demonstrate that measuring protein stability requires a similar holistic analytical framework, as opposed to single-technique assessments that provide misleading conclusions. We reveal information on site-specific ionic liquid–protein interactions, revealing that triflate (the least interacting anion) induces a contraction in the protein size that reduces the barrier to unfolding. Robust frameworks such as this are critical to advancing non-aqueous biocatalysis and avoiding pitfalls associated with single-technique investigations.	May 2020
I04-1-Macromolecular Crystallography (fixed wavelength)	A human protein hydroxylase that accepts D-residues Hwanho Choi , Adam P. Hardy , Thomas M. Leissing , Rasheduzzaman Chowdhury , Yu Nakashima , Wei Ge , Marios Markoulides , John S. Scotti , Philip A. Gerken , Helen Thorbjornsrud , Dahye Kang , Sungwoo Hong , Joongoo Lee , Michael A. Mcdonough , Hwangseo Park , Christopher J. Schofield Communications Chemistry 3 DOI: 10.1038/s42004-020-0290-5 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: Factor inhibiting hypoxia-inducible factor (FIH) is a 2-oxoglutarate-dependent protein hydroxylase that catalyses C3 hydroxylations of protein residues. We report FIH can accept (D)- and (L)-residues for hydroxylation. The substrate selectivity of FIH differs for (D) and (L) epimers, e.g., (D)- but not (L)-allylglycine, and conversely (L)- but not (D)-aspartate, undergo monohydroxylation, in the tested sequence context. The (L)-Leu-containing substrate undergoes FIH-catalysed monohydroxylation, whereas (D)-Leu unexpectedly undergoes dihydroxylation. Crystallographic, mass spectrometric, and DFT studies provide insights into the selectivity of FIH towards (L)- and (D)-residues. The results of this work expand the potential range of known substrates hydroxylated by isolated FIH and imply that it will be possible to generate FIH variants with altered selectivities.	May 2020
I09-Surface and Interface Structural Analysis	Understanding charge compensation mechanisms in Na0.56Mg0.04Ni0.19Mn0.70O2 Le Anh Ma , Felix Massel , Andrew J. Naylor , Laurent-c. Duda , Reza Younesi Communications Chemistry 2 DOI: 10.1038/s42004-019-0227-z Diamond Proposal Number(s): [18974] Open Access Show Abstract ▼ Abstract: Sodium-ion batteries have become a potential alternative to Li-ion batteries due to the abundance of sodium resources. Sodium-ion cathode materials have been widely studied with particular focus on layered oxide lithium analogues. Generally, the capacity is limited by the redox processes of transition metals. Recently, however, the redox participation of oxygen gained a lot of research interest. Here the Mg-doped cathode material P2-Na0.56Mg0.04Ni0.19Mn0.70O2 is studied, which is shown to exhibit a good capacity (ca. 120 mAh/g) and high average operating voltage (ca. 3.5 V vs. Na+/Na). Due to the Mg-doping, the material exhibits a reversible phase transition above 4.3 V, which is attractive in terms of lifetime stability. In this study, we combine X-ray photoelectron spectroscopy, X-ray absorption spectroscopy and resonant inelastic X-ray scattering spectroscopy techniques to shed light on both, cationic and anionic contributions towards charge compensation.	Nov 2019
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Positive functional synergy of structurally integrated artificial protein dimers assembled by Click chemistry Harley L. Worthy , Husam Sabah Auhim , W. David Jamieson , Jacob R. Pope , Aaron Wall , Robert Batchelor , Rachel L. Johnson , Daniel W. Watkins , Pierre Rizkallah , Oliver K. Castell , D. Dafydd Jones Communications Chemistry 2 DOI: 10.1038/s42004-019-0185-5 Diamond Proposal Number(s): [14843] Open Access Show Abstract ▼ Abstract: Construction of artificial higher order protein complexes allows sampling of structural architectures and functional features not accessible by classical monomeric proteins. Here, we combine in silico modelling with expanded genetic code facilitated strain promoted azide-alkyne cycloaddition to construct artificial complexes that are structurally integrated protein dimers and demonstrate functional synergy. Using fluorescent proteins sfGFP and Venus as models, homodimers and heterodimers are constructed that switched ON once assembled and display enhanced spectral properties. Symmetrical crosslinks are found to be important for functional enhancement. The determined molecular structure of one artificial dimer shows that a new long-range polar network comprised mostly of organised water molecules links the two chromophores leading to activation and functional enhancement. Single molecule analysis reveals the dimer is more resistant to photobleaching spending longer times in the ON state. Thus, genetically encoded bioorthogonal chemistry can be used to generate truly integrated artificial protein complexes that enhance function.	Jul 2019
I07-Surface & interface diffraction	Atomistics of pre-nucleation layering of liquid metals at the interface with poor nucleants Sida Ma , Adam J. Brown , Rui Yan , Ruslan L. Davidchack , Paul B. Howes , Chris Nicklin , Qijie Zhai , Tao Jing , Hongbiao Dong Communications Chemistry 2 DOI: 10.1038/s42004-018-0104-1 Diamond Proposal Number(s): [12083, 6663] Open Access Show Abstract ▼ Abstract: Liquid layering at heterogeneous solid/liquid interfaces is a general phenomenon, which provides structural templates for nucleation of crystalline phases on potent nucleants. However, its efficacy near poor nucleants is incompletely understood. Here we use a combination of X-ray crystal truncation rod analysis and ab initio molecular dynamics to probe the pre-nucleation liquid layering at the sapphire–aluminium solid/liquid interface. At the sapphire side, a ~1.6 aluminium-terminated structure develops, and at the liquid side, two pre-nucleation layers emerge at 950 K. No more pre-nucleation layer forms with decreasing temperature indicating that nucleation of crystalline aluminium through layer-by-layer atomic adsorption of liquid atoms is not favoured. Instead, the appearance of stochastically-formed nuclei near the substrate is supported by our experiments. Nucleation on poor nucleants is dominated by the stochastic nucleation events which are substantially influenced by the pre-nucleation layers that determine the surface structure in contact with the nuclei.	Jan 2019

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