Theoretical Physics
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Frank M. F.
De Groot
,
Hebatalla
Elnaggar
,
Federica
Frati
,
Ru-Pan
Wang
,
Mario U.
Delgado-Jaime
,
Michel
Van Veenendaal
,
Javier
Fernandez-Rodriguez
,
Maurits W.
Haverkort
,
Robert J.
Green
,
Gerrit
Van Der Laan
,
Yaroslav
Kvashnin
,
Atsushi
Hariki
,
Hidekazu
Ikeno
,
Harry
Ramanantoanina
,
Claude
Daul
,
Bernard
Delley
,
Michael
Odelius
,
Marcus
Lundberg
,
Oliver
Kuhn
,
Sergey I.
Bokarev
,
Eric
Shirley
,
John
Vinson
,
Keith
Gilmore
,
Mauro
Stener
,
Giovanna
Fronzoni
,
Piero
Decleva
,
Peter
Kruger
,
Marius
Retegan
,
Yves
Joly
,
Christian
Vorwerk
,
Claudia
Draxl
,
John
Rehr
,
Arata
Tanaka
Open Access
Abstract: This review provides an overview of the different methods and computer codes that are used to interpret 2p x-ray absorption spectra of 3d transition metal ions. We first introduce the basic parameters and give an overview of the methods used. We start with the semi-empirical multiplet codes and compare the different codes that are available. A special chapter is devoted to the user friendly interfaces that have been written on the basis of these codes. Next we discuss the first principle codes based on band structure, including a chapter on Density Functional theory based approaches. We also give an overview of the first-principle multiplet codes that start from a cluster calculation and we discuss the wavefunction based methods, including multi-reference methods. We end the review with a discussion of the link between theory and experiment and discuss the open issues in the spectral analysis.
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Apr 2021
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I04-Macromolecular Crystallography
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Open Access
Abstract: The determination of distances between specific points in nucleic acids is essential to understanding their behaviour at the molecular level. The ability to measure distances of 2–10 nm is particularly important: deformations arising from protein binding commonly fall within this range, but the reliable measurement of such distances for a conformational ensemble remains a significant challenge. Using several techniques, we show that electron paramagnetic resonance (EPR) spectroscopy of oligonucleotides spin-labelled with triazole-appended nitroxides at the 2′ position offers a robust and minimally perturbing tool for obtaining such measurements. For two nitroxides, we present results from EPR spectroscopy, X-ray crystal structures of B-form spin-labelled DNA duplexes, molecular dynamics simulations and nuclear magnetic resonance spectroscopy. These four methods are mutually supportive, and pinpoint the locations of the spin labels on the duplexes. In doing so, this work establishes 2′-alkynyl nitroxide spin-labelling as a minimally perturbing method for probing DNA conformation.
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Feb 2020
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I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Diamond Proposal Number(s):
[7299]
Open Access
Abstract: Retroviral integrase (IN) is responsible for two consecutive reactions, which lead to insertion of a viral DNA copy into a host cell chromosome. Initially, the enzyme removes di‐ or trinucleotides from viral DNA ends to expose 3′‐hydroxyls attached to the invariant CA dinucleotides (3′‐processing reaction). Second, it inserts the processed 3′‐viral DNA ends into host chromosomal DNA (strand transfer). Herein, we report a crystal structure of prototype foamy virus IN bound to viral DNA prior to 3′‐processing. Furthermore, taking advantage of its dependence on divalent metal ion cofactors, we were able to freeze trap the viral enzyme in its ground states containing all the components necessary for 3′‐processing or strand transfer. Our results shed light on the mechanics of retroviral DNA integration and explain why HIV IN strand transfer inhibitors are ineffective against the 3′‐processing step of integration. The ground state structures moreover highlight a striking substrate mimicry utilized by the inhibitors in their binding to the IN active site and suggest ways to improve upon this clinically relevant class of small molecules.
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May 2012
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I02-Macromolecular Crystallography
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Wiebke
Fugel
,
Anselm Erich
Oberholzer
,
Bernhard
Gschloessl
,
Ron
Dzikowski
,
Narkiss
Pressburger
,
Lutz
Preu
,
Laurence H.
Pearl
,
Blandine
Baratte
,
Morgane
Ratin
,
Ilya
Okun
,
Christian
Doerig
,
Sebastian
Kruggel
,
Thomas
Lemcke
,
Laurent
Meijer
,
Conrad
Kunick
Diamond Proposal Number(s):
[8015]
Abstract: Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC50 values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.
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Jan 2013
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I12-JEEP: Joint Engineering, Environmental and Processing
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A.
Koko
,
S.
Singh
,
S.
Barhli
,
T.
Connolley
,
N. T.
Vo
,
T.
Wigger
,
D.
Liu
,
Y.
Fu
,
J.
Réthoré
,
J.
Lechambre
,
J.-Y.
Buffiere
,
T. J.
Marrow
Diamond Proposal Number(s):
[12585]
Open Access
Abstract: The propagation rate of a fatigue crack in a nodular cast iron, loaded in cyclic tension, has been studied in situ by X-ray computed tomography and digital volume correlation. The semi-elliptical crack initiated from an asymmetric corner notch and evolved to a semi-circular shape, initially with a higher growth rate towards one edge of the notch before the propagation rate along the crack front became essentially independent of po-sition. The phase congruency of the displacement field was used to measure the crack shape. The three-dimensional stress intensity factors were calculated via a linear elastic finite element model that used the displacement fields around the crack front as the boundary conditions. Closure of the crack tip region was observed. The cyclic change in the local mode I opening of the crack tip determined the local fatigue crack propaga-tion rate along the crack front.
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May 2023
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I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
I04-Macromolecular Crystallography
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Andrea
Testa
,
Xavier
Lucas
,
Guilherme V.
Castro
,
Kwok-Ho
Chan
,
Jane E.
Wright
,
Andrew C.
Runcie
,
Morgan S.
Gadd
,
William T. A.
Harrison
,
Eun-Jung
Ko
,
Daniel
Fletcher
,
Alessio
Ciulli
Diamond Proposal Number(s):
[10071, 14980]
Open Access
Abstract: Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e. fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-L-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy and quantum mechanical calculations are consistent with fluorination at C3 having negligible effects on the hydrogen bond donor capacity of the C4 hydroxyl, but inverting the natural preference of Hyp from C4-exo to C4-endo pucker. In spite of this, F-Hyps still bind to the von Hippel-Lindau (VHL) E3 ligase, which naturally recognizes C4-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3R,4S)-F-Hyp over the corresponding (3S,4S) epimer by VHL. We show that (3R,4S)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia inducible factor 1 alpha (HIF-1α) substrate peptides as well as peptidomimetic ligands that form part of PROTAC (PROteolysis TArgeting Chimera) conjugates for targeted protein deg-radation. Despite a weakened affinity, Hyp substitution with (3S,4S)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary Kd for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists and drug discoverers alike.
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Jun 2018
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I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Luís A. R.
Carvalho
,
Vanessa T.
Almeida
,
Jose A.
Brito
,
Kenneth M.
Lum
,
Tânia F.
Oliveira
,
Rita C.
Guedes
,
Lídia M.
Gonçalves
,
Susana D.
Lucas
,
Benjamin F.
Cravatt
,
Margarida
Archer
,
Rui
Moreira
Diamond Proposal Number(s):
[20161]
Abstract: 3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-β-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.
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Mar 2020
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I12-JEEP: Joint Engineering, Environmental and Processing
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Diamond Proposal Number(s):
[8519, 9036]
Abstract: Nuclear graphite has a complex porous microstructure, which depends on raw materials and manufacturing process; porosity can change with radiolytic oxidation and also in the absence of oxidation with very high neutron fluences. Porosity directly affects the fracture process and the graphite tensile strength. To understand the effects of porosity on component strength and its relation to small specimen data, microstructure sensitive models are needed that can simulate the statistics of strength of porous microstructures, also addressing size and strain gradients effects such as notches. This requires multi-scale models that capture the key microstructural features with sufficient fidelity, and also with sufficient computational economy to simulate component behaviour. To achieve this, an innovative technique to calculate the elastic stress distribution in a 3D porous solid under uniaxial or biaxial tension has been developed that uses Cellular Automata. Synthetic microstructures with arbitrary distributions of pore sizes and shapes are created that simulate realistic microstructures; a fracture algorithm simulates failure initiation and crack growth. The model calculates the tensile strength of a microstructure volume for any arbitrary failure criteria; the critical strain energy release rate is used as an example to demonstrate how porosity affects the fracture process. The presented Cellular Automata (CA) model is at least an order of magnitude more efficient than finite element methods of equivalent discretisation; CA are also scale independent and well suited for parallel computing. This would allow large volumes of representative microstructures to be simulated, with a Monte-Carlo based approach to investigate strength variability.
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Jan 2016
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B16-Test Beamline
Detectors
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Open Access
Abstract: 3D detectors are a novel variety of photodiode radiation detector, invented by
Parker, Kenney and Segal (1997). Instead of having n- and p-type contacts on
the front and back surfaces of a silicon substrate, like a standard photodiode, they
have columns of doped material passing through the thickness of the silicon. This
structure means that the detector can combine a reasonable substrate thickness
with a very small electrode spacing, resulting in a low depletion voltage, fast charge
collection and low charge sharing.
These detectors have a couple of promising applications. Their fast charge collection
and low depletion voltage should make them very radiation-tolerant. So, they
could be used for future particle physics experiments at the Super Large Hadron
Collider (SLHC), where high levels of radiation damage are expected. Also, their
low charge sharing means they could potentially improve X-ray diffraction measurements
at synchrotrons such as Diamond Light Source. This would allow these
experiments, for example, to determine the structures of biological molecules more
accurately.
However, before 3D devices can be used in practical experiments, their design and
fabrication must be optimised to ensure that reliable, high-performance detectors
can be produced on a reasonably large scale. The aim of this thesis is to evaluate
and understand the behaviour of a variety of 3D detectors using a combination of
lab tests and computer simulations. Using these results, future fabrication runs can
then be re-designed to improve their performance.
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Apr 2009
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B16-Test Beamline
Optics
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E. N.
Gimenez-navarro
,
J.
Marchal
,
K. J. S.
Sawhney
,
L.
Alianelli
,
M.
Lozano
,
Giulio
Pellegrini
,
C.
Fleta
,
V.
O'shea
,
R.
Bates
,
C.
Parkes
,
A.
Mac Raighne
,
D.
Maneuski
,
N.
Tartoni
Diamond Proposal Number(s):
[520]
Abstract: Three-dimensional (3D) photodiode detectors offer advantages over standard planar photodiodes in a wide range of applications. The main advantage of these sensors for X-ray imaging is their reduced charge sharing between adjacent pixels, which could improve spatial and spectral resolution. However, a drawback of 3D sensors structures is the loss of detection efficiency due to the presence in the pixel structure of heavily doped electrode columns which are insensitive to X-ray. In this work two types of 3D silicon detectors: n-type wafer with hole collecting readout-columns (n-type) and p-type wafer with electron collecting readout-columns (p-type), bump-bounded to a Medipix2 read-out chip were characterized with a 14.5 keV micro-focused X-ray beam from a synchrotron. Measurements of the detection efficiency and the charge sharing were performed at different bias voltages and Medipix2 energy thresholds and compared with those of a standard planar silicon sensor.
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Jul 2010
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