B21-High Throughput SAXS
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Thomas
Lundbäck
,
Vijay
Chandrasekar
,
Chendi
Gu
,
Hyoungseok
Ju
,
Robyn
Mcadam
,
Maria
Palomero
,
Kasim
Sader
,
Bradley
Peter
,
Lisa
Wissler
,
Philip
Nevin
,
Edmund
Foster
,
Tanguy
Jamier
,
Pravallika
Manjappa
,
Carina
Johansson
,
Jenny
Sandmark
,
Mei
Ding
,
Anette
Persson-Kry
,
Sanhita
Mitra
,
Tugce
Munise Satir
,
Bilada
Bilican
,
Mirko
Messa
,
Graham
Fraser
,
John
Linley
,
Helen
Plant
,
Rachel
Moore
,
Tina
Seifert
,
Michael
Lerche
,
Carina
Raynochek
,
Ewa
Nilsson
,
Nour
Majbour
,
Richard
Lucey
,
Taiana
Maia De Oliveira
,
Qi
Wang
,
Iain
Chessell
,
Perla
Breccia
,
Rebecca
Jarvis
Open Access
Abstract: The sterile alpha and TIR motif containing 1 (SARM1) enzyme is a key driver of axonal degeneration in response to injury, making it an attractive target for treating chemotherapy-induced peripheral neuropathy (CIPN) and other nervous system diseases. In this study, we identified and optimised a class of base-exchange inhibitors (BEXi) targeting human SARM1 and explored their molecular interactions and conformational effects using cryo-EM, HDX-MS and SAXS. Although BEXi produced robust inhibition across all biochemical and cellular assay formats, application at sub-inhibitory concentrations consistently led to paradoxical SARM1 activation, and in neuronal assays, accelerated neurite degeneration. Further analysis showed that BEXi only delayed, rather than prevented, neurite degeneration when applied to primary neuronal cells, even at exceedingly high inhibitor concentrations. These results prompted us to discontinue BEXi development in favour of alternative strategies, underscoring the complexity of SARM1 as a therapeutic target and the need for comprehensive, mechanistically informed screening cascades.
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May 2026
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labSAXS-Offline SAXS and Sample Environment Development
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Ikechukwu D.
Nwosu
,
Lujo
Matasović
,
Tárcius N.
Ramos
,
Nguyen Le
Phuoc
,
Giacomo
Londi
,
Alexander J.
Gillett
,
Daniel T. W.
Toolan
,
Charles T.
Smith
,
George F. S.
Whitehead
,
Mireille
Blanchard-Desce
,
Jonathan
Daniel
,
Mikko
Linnolahti
,
Yoann
Olivier
,
Alexander S.
Romanov
Diamond Proposal Number(s):
[40538]
Open Access
Abstract: Advanced photonic materials showing two-photon absorption (2PA) have been widely explored to develop three-dimensional imaging, micro and nanofabrication, all-optical switching, lithography on a nanoscale and many other enabling technologies. These all require nonlinear absorption chromophores with intrinsic 2PA cross-sections and long-term photo- and thermal stability. Here, we disclose the very first example of the dipolar carbene-metal-amide (CMA) material showing a enhanced 2PA cross-section up to 105 GM. Overall molecular design considerations such as extended π-conjugation (to increase polarizability), minimizing the singlet-triplet energy gap (ΔEST), and using heavy metal atoms are the first design principles to obtain bright one- and two-photon excited thermally activated delayed fluorescence (TADF) material, showing one of the highest radiative rate of 2.18·106 s-1 across CMA materials. Bright red CMA 2P-TADF material shows excellent photostability (LT50 = 3 h) to 20 mW femtosecond pulsed laser excitation at 1000 nm, encouraging further CMA exploration for future applications in advanced photonic technologies requiring third-order nonlinear optical properties.
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Feb 2026
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I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[31800]
Open Access
Abstract: Solenoid proteins are elongated tandem repeat proteins with diverse biological functions, making them attractive targets for protein design. Advances in machine learning have transformed our understanding of sequence-structure relationships, enabling new approaches for de novo protein design. Here, we present an in silico evolution platform that couples a solenoid discriminator network with AlphaFold2 as an oracle within a genetic algorithm. Starting from random sequences, we design α-, β-, and αβ-solenoid backbones, generating structures that span natural and novel solenoid space. We experimentally characterise 41 solenoid designs, with α-solenoids consistently folding as intended, including one structurally validated design that closely matches the design model. All β-solenoids initially failed, reflecting the difficulty of designing β-strand majority proteins. By introducing terminal capping elements and refining designs based on earlier experimental screens, we generate two β-solenoids that have biophysical properties consistent with their designs. Our approach achieves fold-specific hallucination-based design without depending on explicit structural templates.
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Dec 2025
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labSAXS-Offline SAXS and Sample Environment Development
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Diamond Proposal Number(s):
[40538]
Open Access
Abstract: A facile, stepwise synthetic route has been developed to access symmetric double [5]helicene diimides and their planar nanographene diimide counterparts via a C-shaped asymmetric [5]helicene. The synthetic strategy employs benzannulation and Scholl reaction methodologies to achieve progressive π-extension, yielding a new class of n-type rylene diimides with reversible redox characteristics. These helical and planar diimides exhibit variable crosswise π-conjugation and structural tunability, resulting in emission wavelengths that can be tailored alongside enhanced photoluminescence quantum yields—from 12% for the S-shaped diimide, to 57% for the C-shaped intermediate, and up to 63% for the fully planar nanographene diimide. Such properties make them promising candidates for quantum photonics, particularly as single-photon emitters. Photophysical properties, including time-resolved photoluminescence and transient absorption spectroscopy, reveal correlations between molecular structure, exciton dynamics, and emission behaviour. Notably, these helical rylene diimides demonstrate high photoluminescence efficiency in the solid state, reaching up to 32%, positioning them as strong contenders for next-generation optoelectronic devices.
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Nov 2025
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I22-Small angle scattering & Diffraction
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Diamond Proposal Number(s):
[37889]
Open Access
Abstract: Despite being the most abundant sustainable energy resource, solar energy still faces major challenges in efficient capture and long-term storage. Molecular Solar Thermal Energy Storage (MOST) systems address this issue by employing photoswitchable molecules that absorb sunlight and store energy through reversible isomerization, cyclization or other intramolecular rearrangements. Azobenzenes are attractive due to their well-characterized photoresponsive behavior; however, conventional systems are hindered by low energy density, limited energy storage duration, and a reliance on organic solvents. Here, we present the Micellar Solar Thermal Energy Storage system (MIST) approach based on micellar aggregates that operate effectively across aqueous dispersions and gel states. These systems exhibit progressively enhanced energy storage lifetimes with increasing degrees of self-assembly, while delivering competitive energy densities. The thermal stability arises from restricted molecular mobility within the self-assembled structures and is enhanced on gelation, extending the calculated thermal half-life of the cis isomer from 148 days in dimethyl sulfoxide (DMSO), to 233 days in water, and to 12.8 years in the gel state. Compared to previous azobenzene-based MOST systems, our MIST approach offers significantly extended energy storage durations and improved material processability, including water-compatible formulations and, macroscopic heat release in the gel state (up to 5.7 °C).
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Nov 2025
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I11-High Resolution Powder Diffraction
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Diamond Proposal Number(s):
[34800]
Open Access
Abstract: Layered crystal structures are commonly found across organic and inorganic material systems. When in-plane atomic arrangement remains (nearly) identical, a stacking variation of these layers may result in twinning, planar disorder, or polytypes, a form of polymorphism derived from altering stacking sequences. In this work, we use multi-dimensional electron diffraction (ED) modalities to explore the microstructure of xanthine, an archetypal purine base with a layered crystal structure. Firstly, we identify and characterise the twin operator relating domains of Form I xanthine. We then solve the structure of a new xanthine polymorph, revealing that it is a polytype of Form I. Finally, interfaces between twin and polytype domains are visualised, whilst streaking in the diffraction patterns reveals the presence of planar disorder. Given these observations in the xanthine system, this work suggests that disorder on the nanoscale may be a commonly occurring phenomenon in layered organic molecular crystals.
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Nov 2025
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I20-Scanning-X-ray spectroscopy (XAS/XES)
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Lewis G.
Parker
,
Frances K.
Towers Tompkins
,
Jake M.
Seymour
,
Najaat
Alblewi
,
Ekaterina
Gousseva
,
Megan R.
Daw
,
Shusaku
Hayama
,
Richard P.
Matthews
,
Adam E. A.
Fouda
,
Joshua D.
Elliott
,
Christopher D.
Smith
,
Kevin R. J.
Lovelock
Diamond Proposal Number(s):
[24305, 28565, 30597, 33520, 36798]
Open Access
Abstract: Diorganozinc reagents (ZnR2, e.g. R = Et, Ph, C6F5) are widely used as Lewis acid catalysts or Lewis base reagents in their own right. However, descriptors for predicting the influence of the R substituent on ZnR2 Lewis acidity/basicity are very sparse. This is because ZnR2 liquid-phase speciation and electronic structure are unknown to date due to zinc’s ‘spectroscopically quiet’ nature and inability to measure ‘at zinc’. Here, we identify the geometric structures of ZnR2 in weakly coordinating solvents, demonstrating that electronic structure factors will dominate reactivity. We quantify the electronic structure properties that dictate ZnR2 Lewis acidity/basicity using three newly developed zinc-specific descriptors by combining the results from three zinc-specific X-ray spectroscopy methods and calculations. We provide accessible methods to pre-screen ZnR2 reactivity. Furthermore, our X-ray spectroscopy toolkit offers opportunities to develop liquid-phase descriptors that dictate reactivity for other zinc species, e.g. zinc bis-amides, battery electrolytes and enzymes.
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Oct 2025
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B23-Circular Dichroism
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Diamond Proposal Number(s):
[33225]
Open Access
Abstract: Deep eutectic solvents (DESs) have emerged as powerful environments to enhance enzymatic reactions, formulate therapeutic proteins, and develop protein-based biomaterials. Despite the wide range of properties that could be achievable through the compositional design of DESs, protein solubilization only happens in a relatively narrow range of hydrophilic DESs. Here, we use surface-modification for the generalized solubilization of proteins in both hydrophilic and hydrophobic DESs. Using surface-modified myoglobin as a model, we show that both DES polarity and hydrogen bond capacity play important roles in dictating the conformational state of the protein. In the hydrophilic DES the protein displays a near-native conformation with an improvement of the thermal stability of + 28 °C compared to aqueous solutions. In contrast, hydrophobic DESs stabilize partially folded intermediates which can refold from temperatures as high as 190 °C. As such, our approach provides a platform to generalize protein incorporation into anhydrous DESs that could be exploited in biocatalysis, biomolecule stabilization, and biomaterials.
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Jun 2025
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I24-Microfocus Macromolecular Crystallography
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Diamond Proposal Number(s):
[11265]
Open Access
Abstract: Botulinum neurotoxins are the causative agents of botulism, a lethal paralytic disease, but are also one of the most commonly used therapeutics for the treatment of numerous neuromuscular conditions. These toxins recognise motor nerve terminals with high specificity and affinity by using a dual binding mechanism involving gangliosides and protein receptors. The initial recognition of gangliosides is crucial for the toxins’ potency. In this study, we employed a synaptosome-binding screening strategy to identify BoNT/A mutants with enhanced ganglioside-binding which translated into improved potency. X-ray crystallography and receptor-binding assays were used to elucidate the molecular mechanisms underlying the increased affinity or altered ganglioside selectivity of these mutants. Our findings provide a basis for the development of BoNT/A variants with enhanced therapeutic potential.
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Jun 2025
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I04-1-Macromolecular Crystallography (fixed wavelength)
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Yeojin
Kim
,
Aleksandar
Lučić
,
Christopher
Lenz
,
Frederic
Farges
,
Martin P.
Schwalm
,
Krishna
Saxena
,
Thomas
Hanke
,
Peter G.
Marples
,
Jasmin C.
Aschenbrenner
,
Daren
Fearon
,
Frank
Von Delft
,
Andreas
Kramer
,
Stefan
Knapp
Diamond Proposal Number(s):
[29658]
Open Access
Abstract: Tripartite motif-containing protein 21 (TRIM21), and particularly its PRY-SPRY protein interaction domain, plays a critical role in the immune response by recognizing intracellular antibodies targeting them for degradation. In this study, we performed a crystallographic fragment screening (CFS) campaign to identify potential small molecule binders targeting the PRY-SPRY domain of TRIM21. Our screen identified a total of 109 fragments binding to TRIM21 that were distributed across five distinct binding sites. These fragments have been designed to facilitate straightforward follow-up chemistry, making them ideal starting points for further chemical optimization. A subsequent fragment merging approach demonstrated improved activity. To enable functional validation of compounds with full length human TRIM21, we established a NanoBRET assay suitable for measuring target engagement to the main Fc binding site in life cells. The high-resolution structural data and observed binding modes across the different sites highlight the versatility of the PRY-SPRY domain as a target for small-molecule intervention. The presented data provide a solid foundation for structure-guided ligand design, enabling the rational design of more potent and selective compounds, with the goal to develop bivalent molecules such as Proteolysis Targeting Chimeras (PROTACs).
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Jun 2025
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