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Open Access
Abstract: X-ray photoemission and X-ray absorption spectroscopy are important techniques to characterize chemical bonding at surfaces and are often used to identify the strength and nature of adsorbate–substrate interactions. In this study, we judge the ability of X-ray spectroscopic techniques to identify different regimes of chemical bonding at metal–organic interfaces. To achieve this, we sample different interaction strength regimes in a comprehensive and systematic way by comparing two topological isomers, azulene and naphthalene, adsorbed on three metal substrates with varying reactivity, namely the (111) facets of Ag, Cu, and Pt. Using density functional theory, we simulate core-level binding energies and X-ray absorption spectra of the molecular carbon species. The simulated spectra reveal three distinct characteristics based on the molecule-specific spectral features which we attribute to types of surface chemical bonding with varying strength. We find that weak physisorption only leads to minor changes compared to the gas-phase spectra, weak chemisorption leads to charge transfer and significant spectral changes, and strong chemisorption leads to a loss of the molecule-specific features in the spectra. The classification we provide is aimed at assisting interpretation of experimental X-ray spectra for complex metal–organic interfaces.
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Jan 2023
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I22-Small angle scattering & Diffraction
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Mario
Gonzalez-Jimenez
,
Trent
Barnard
,
Ben A.
Russell
,
Nikita V.
Tukachev
,
Uroš
Javornik
,
Laure-Anne
Hayes
,
Andrew J.
Farrell
,
Sarah
Guinane
,
Hans M.
Senn
,
Andrew J.
Smith
,
Martin
Wilding
,
Gregor
Mali
,
Motohiro
Nakano
,
Yuji
Miyazaki
,
Paul
Mcmillan
,
Gabriele C.
Sosso
,
Klaas
Wynne
Diamond Proposal Number(s):
[28529]
Open Access
Abstract: A common feature of glasses is the “boson peak”, observed as an excess in the heat capacity over the crystal or as an additional peak in the terahertz vibrational spectrum. The microscopic origins of this peak are not well understood; the emergence of locally ordered structures has been put forward as a possible candidate. Here, we show that depolarised Raman scattering in liquids consisting of highly symmetric molecules can be used to isolate the boson peak, allowing its detailed observation from the liquid into the glass. The boson peak in the vibrational spectrum matches the excess heat capacity. As the boson peak intensifies on cooling, wide-angle x-ray scattering shows the simultaneous appearance of a pre-peak due to molecular clusters consisting of circa 20 molecules. Atomistic molecular dynamics simulations indicate that these are caused by over-coordinated molecules. These findings represent an essential step toward our understanding of the physics of vitrification.
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Jan 2023
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B18-Core EXAFS
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Diamond Proposal Number(s):
[30958]
Open Access
Abstract: The heterogeneous solid–gas reactions of crystals of [Rh(L2)(propene)][BArF4] (1, L2 = tBu2PCH2CH2PtBu2) with H2 and propene, 1-butene, propyne, or 1-butyne are explored by gas-phase nuclear magnetic resonance (NMR) spectroscopy under batch conditions at 25 °C. The temporal evolution of the resulting parahydrogen-induced polarization (PHIP) effects measures catalytic flux and thus interrogates the efficiency of catalytic pairwise para-H2 transfer, speciation changes in the crystalline catalyst at the molecular level, and allows for high-quality single-scan 1H, 13C NMR gas-phase spectra for the products to be obtained, as well as 2D-measurements. Complex 1 reacts with H2 to form dimeric [Rh(L2)(H)(μ-H)]2[BArF4]2 (4), as probed using EXAFS; meanwhile, a single-crystal of 1 equilibrates NMR silent para-H2 with its NMR active ortho isomer, contemporaneously converting into 4, and 1 and 4 each convert para-H2 into ortho-H2 at different rates. Hydrogenation of propene using 1 and para-H2 results in very high initial polarization levels in propane (>85%). Strong PHIP was also detected in the hydrogenation products of 1-butene, propyne, and 1-butyne. With propyne, a competing cyclotrimerization deactivation process occurs to afford [Rh(tBu2PCH2CH2PtBu2)(1,3,4-Me3C6H3)][BArF4], while with 1-butyne, rapid isomerization of 1-butyne occurs to give a butadiene complex, which then reacts with H2 more slowly to form catalytically active 4. Surprisingly, the high PHIP hydrogenation efficiencies allow hyperpolarization effects to be seen when H2 is taken directly from a regular cylinder at 25 °C. Finally, changing the chelating phosphine to Cy2PCH2CH2PCy2 results in initial high polarization efficiencies for propene hydrogenation, but rapid quenching of the catalyst competes to form the zwitterion [Rh(Cy2PCH2CH2PCy2){η6-(CF3)2(C6H3)}BArF3].
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Jan 2023
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B21-High Throughput SAXS
I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Laura C.
Clark
,
Kate E.
Atkin
,
Fiona
Whelan
,
Andrew S.
Brentnall
,
Gemma
Harris
,
Aisling M.
Towell
,
Johan P.
Turkenburg
,
Yan
Liu
,
Ten
Feizi
,
Samuel C.
Griffiths
,
Joan A.
Geoghegan
,
Jennifer R.
Potts
Diamond Proposal Number(s):
[7864, 18598]
Open Access
Abstract: Staphylococcus aureus and Staphylococcus epidermidis are frequently associated with medical device infections that involve establishment of a bacterial biofilm on the device surface. Staphylococcal surface proteins Aap, SasG and Pls are members of the Periscope Protein class and have been implicated in biofilm formation and host colonisation; they comprise a repetitive region (“B region”) and an N-terminal host colonisation domain within the “A region”, predicted to be a lectin domain. Repetitive E-G5 domains (as found in Aap, SasG and Pls) form elongated ‘stalks’ that would vary in length with repeat number, resulting in projection of the N-terminal A domain variable distances from the bacterial cell surface. Here, we present the structures of the lectin domains within A regions of SasG, Aap and Pls and a structure of the Aap lectin domain attached to contiguous E-G5 repeats, suggesting the lectin domains will sit at the tip of the variable length rod. We demonstrate that these isolated domains (Aap, SasG) are sufficient to bind to human host desquamated nasal epithelial cells. Previously, proteolytic cleavage or a deletion within the A domain have been reported to induce biofilm formation; the structures suggest a potential link between these observations. Intriguingly, whilst the Aap, SasG and Pls lectin domains bind a metal ion, they lack the non-proline cis peptide bond thought to be key for carbohydrate binding by the lectin fold. This suggestion of non-canonical ligand binding should be a key consideration when investigating the host cell interactions of these bacterial surface proteins.
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Jan 2023
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B21-High Throughput SAXS
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Diamond Proposal Number(s):
[29806]
Open Access
Abstract: Small-angle X-ray scattering (SAXS) can be used for structural determination of biological macromolecules and polymers in their native states (e.g. liquid phase). This means that the structural changes of (bio-)polymers, such as proteins and DNA, can be monitored in situ to understand their sensitivity to changes in chemical environments. In an attempt to improve the reliability of such experiments, the reduction of radiation damage occurring from exposure to X-rays is required. One such method, is to use scavenger molecules to protect macromolecules against radicals produced during radiation exposure, such as reactive oxygen species (ROS). In this study we investigate the feasibility of applying the compatible solute, osmolyte and radiation protector Ectoine (THP(B)), as a scavenger molecule during SAXS measurements of the single-stranded DNA-binding protein Gene-V Protein (G5P/GVP). In this case, we monitor the radiation induced changes of G5P during bio-SAXS measurments and the resulting microscopic energy-damage relation was determined from microdosimetric calculations by Monte-Carlo based particle scattering simulations with TOPAS/Geant4 and a custom target-model. This resulted in a median-lethal energy deposit of pure G5P at 4 mg mL−1 of E1/2 = 7 ± 5 eV, whereas a threefold increase of energy-deposit was needed under the presence of Ectoine to reach the same level of damage. This indicates that Ectoine increases the possible exposure time before radiation-damage to G5P is observed. Furthermore, the dominant type of damage shifted from aggregation in pure solutions towards a fragmentation for solutions containing Ectoine as a cosolute. These results are interpreted in terms of indirect radiation damage by reactive secondary species, as well as post-irradiation effects, related to preferential-exclusion of the cosolute from the protein surface. Hence, Ectoine is shown to provide a non-disturbing way to improve structure-determination of proteins via bio-SAXS in future studies.
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Jan 2023
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Detectors
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J.
Correa
,
M.
Mehrjoo
,
R.
Battistelli
,
F.
Lehmkühler
,
A.
Marras
,
C. B.
Wunderer
,
T.
Hirono
,
V.
Felk
,
F.
Krivan
,
S.
Lange
,
I.
Shevyakov
,
V.
Vardanyan
,
M.
Zimmer
,
M.
Hoesch
,
K.
Bagschik
,
N.
Guerrini
,
B.
Marsh
,
I.
Sedgwick
,
G.
Cautero
,
L.
Stebel
,
D.
Giuressi
,
R. H.
Menk
,
A.
Greer
,
T.
Nicholls
,
W.
Nichols
,
U.
Pedersen
,
P.
Shikhaliev
,
N.
Tartoni
,
H. J.
Hyun
,
S. H.
Kim
,
S. Y.
Park
,
K. S.
Kim
,
F.
Orsini
,
F. J.
Iguaz
,
F.
Büttner
,
B.
Pfau
,
E.
Plönjes
,
K.
Kharitonov
,
M.
Ruiz-Lopez
,
R.
Pan
,
S.
Gang
,
B.
Keitel
,
H.
Graafsma
Open Access
Abstract: The PERCIVAL detector is a CMOS imager designed for the soft X-ray regime at photon sources. Although still in its final development phase, it has recently seen its first user experiments: ptychography at a free-electron laser, holographic imaging at a storage ring and preliminary tests on X-ray photon correlation spectroscopy. The detector performed remarkably well in terms of spatial resolution achievable in the sample plane, owing to its small pixel size, large active area and very large dynamic range; but also in terms of its frame rate, which is significantly faster than traditional CCDs. In particular, it is the combination of these features which makes PERCIVAL an attractive option for soft X-ray science.
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Jan 2023
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I15-Extreme Conditions
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Open Access
Abstract: Geothermal heat from the Earth`s crust is a source of natural and renewable energy. This energy can be extracted and used for generating electricity and heating of houses in the winter months. However, in order to extract energy from a well, we need to use material that can sustain contact with geothermal steam and is resistant to corrosion of the geothermal fluid and non-condensing gases such as hydrogen sulfide (H2S) and carbon dioxide (CO2), chloride ions (Cl−), and hydrogen fluoride (HF). An interesting alternative to today's materials are bimetals, composed of two different materials where the layer in contact with the aggressive environment is made of a noble material, while the outer layer (typically low-carbon steel) strengthens the composite and additionally provides good weldability.
This paper presents the microstructure, phase composition, and distribution of residual stresses of the bimetallic system nickel-chromium-molybdenum alloy (Alloy 625) cladded on the ferritic pressure vessel steel P355NH base material.
The bimetal has been prepared by explosion welding and is its use is geared for transport of highly corrosive media and as a material for heat exchangers, condensers, etc.
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Jan 2023
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Sudarshan
Murthy
,
Maria Giulia
Nizi
,
Mirko M.
Maksimainen
,
Serena
Massari
,
Juho
Alaviuhkola
,
Barbara E.
Lippok
,
Chiara
Vagaggini
,
Sven T.
Sowa
,
Albert
Galera-Prat
,
Yashwanth
Ashok
,
Harikanth
Venkannagari
,
Renata
Prunskaite-Hyyryläinen
,
Elena
Dreassi
,
Bernhard
Lüscher
,
Patricia
Korn
,
Oriana
Tabarrini
,
Lari
Lehtio
Diamond Proposal Number(s):
[23346, 26794, 19951]
Open Access
Abstract: We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21 (OUL243) and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.
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Jan 2023
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Stefan
Gahbauer
,
Galen J.
Correy
,
Marion
Schuller
,
Matteo P.
Ferla
,
Yagmur Umay
Doruk
,
Moira
Rachman
,
Taiasean
Wu
,
Morgan
Diolaiti
,
Siyi
Wang
,
R. Jeffrey
Neitz
,
Daren
Fearon
,
Dmytro S.
Radchenko
,
Yurii S.
Moroz
,
John J.
Irwin
,
Adam R.
Renslo
,
Jenny C.
Taylor
,
Jason E.
Gestwicki
,
Frank
Von Delft
,
Alan
Ashworth
,
Ivan
Ahel
,
Brian K.
Shoichet
,
James S.
Fraser
Open Access
Abstract: The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.
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Jan 2023
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I04-Macromolecular Crystallography
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Michelle H.
Nelson
,
Sara
Fritzell
,
Robert
Miller
,
Doreen
Werchau
,
Danielle
Van Citters
,
Anneli
Nilsson
,
Lynda
Misher
,
Lill
Ljung
,
Robert
Bader
,
Adnan
Deronic
,
Allison G.
Chunyk
,
Lena
Schultz
,
Laura A.
Varas
,
Nadia
Rose
,
Maria
Håkansson
,
Jane
Gross
,
Christina
Furebring
,
Peter
Pavlik
,
Anette
Sundstedt
,
Niina
Veitonmäki
,
Hilario J.
Ramos
,
Anna
Säll
,
Anna
Dahlman
,
David
Bienvenue
,
Laura
Von Schantz
,
Catherine J.
Mcmahan
,
Maria
Askmyr
,
Gabriela
Hernandez-Hoyos
,
Peter
Ellmark
Diamond Proposal Number(s):
[23282]
Open Access
Abstract: 4–1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4–1BB on tumor-specific cytotoxic T cells makes 4–1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4–1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4–1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4–1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4–1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4–1BB–mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
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Jan 2023
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