bluuebunny/crossref_metadata_2025 huggingface dataset:
Overcoming drug-resistant malaria through rational drug design in cytochrome bc1
Authors: Capper Michael , O'Neill Paul , Biagini Giancarlo , Hasnain Samar , Antonyuk Svetlana
Published: November 2015

Over three billion people live in regions affected by malaria and there are over one million deaths each year [1]. Malaria is caused by the Plasmodium parasite and various drugs are currently used in both treatment and prophylaxis but resistant strains are rapidly emerging. One of the most commonly used anti-malarial drugs is Atovaquone, a hydroxynapthoquinone that is currently used in combination with Proguanil and sold as Malarone™. Atovaquone targets cytochrome bc1 (Complex III, ubiquinol-cytochrome c oxidoreductase), a multi subunit electron transfer protein complex embedded in the inner mitochondrial membrane [2]. Drug resistance rises through a single point mutation in cytochrome b at the Qo site, one of two quinone binding sites. By visualising compounds bound to cytochrome bc1 through x-ray crystallography, it may be possible to modify the compounds to both bind stronger and more specifically. We have worked on compounds that recently failed phase I clinical trials due to cross-reactivity with human cytochrome bc1 [3]. Our structural studies have shown that these compounds appear to bind at the Qi site, which would overcome current drug-resistant strains. Further work here could produce a novel class of anti-malarial drug.
How bacterial effectors hijack small GTPases to divert membrane traffic
Authors: Cherfils Jacqueline , Folly-Klan Marcia , Campanacci Valérie
Published: November 2015

Membrane traffic, which is the "cellular postal service" that shuttles biomolecules around the cell and organizes the structure of organelles, is among the primary targets of effectors injected by intracellular pathogenic bacteria to invade their host and avoid from being destroyed. I will present our recent structural and biochemical studies of effectors from Legionella pneumophila (the bacteria that causes the legionnaire's disease, a severe pneumonia) that divert membrane traffic to generate a membrane-bound vacuole where the pathogen hides and replicates. One of these effectors, AnkX, is a FIC domain-containing toxin that alters the functions of a Rab GTPase involved in vesicular traffic at the endoplasmic reticulum, by covalent attachment of a phosphocholine molecule. The other one, RalF, functions as an illegitimate guanine nucleotide exchange factor to activate an Arf GTPase on the vacuole. Our studies showed how AnkX binds and processes CDP-choline to transfer phosphocholine onto Rab1 [1], and uncover a novel membrane sensor in RalF that controls its localization and activity [2]
Dealing with Aperiodic Protein Crystal Structures
Authors: Borgstahl Gloria
Published: November 2015

Protein crystals can be aperiodic. They will diffract X-rays, and are therefore a crystal, but their diffraction is not periodic. This means that their diffraction pattern cannot be simply be indexed by a typical three-dimensional unit cell and space group. Aperiodic crystals include "quasi-crystals" as well as "modulated" crystals. In the latter case, the modulation can be positional or occupational and these modulations can be incommensurate with the normal periodic lattice [1]. An overview of aperiodic protein crystal diffraction will be presented with examples. The discussion will then focus on the characteristics of incommensurately modulated crystals followed by a more detailed discussion of how to solve these crystals. The following details of structure solution will be presented: (1) data collection perils; (2) specialized diffraction data processing in (3+1)D space using a q-vector [2]; (3) how to get an approximation of the structure in 3D space; (4) the assignment of the (3+1)D space group; and the ultimate (5) crystallographic refinement in superspace[3]. Future directions and needs will be discussed.
First steps towards time-resolved 'in-house' X-ray diffraction experiments
Authors: Kaminski Radoslaw , Benedict Jason , Trzop Elzbieta , Jarzembska Katarzyna , Fournier Bertrand , Coppens Philip
Published: November 2015

High-intensity X-ray sources, such as synchrotrons or X-ray free electron lasers, providing up to 100 ps time-resolution allow for studying very short-lived excited electronic states in molecular crystals. Some recent examples constitute investigations of Rh...Rh bond shortening,[1] or metal-to-ligand charge transfer processes in CuI complexes.[2] Nevertheless, in cases in which the lifetime of excited state species exceeds 10 μs it is now possible, due to the dramatic increase in the brightness of X-ray sources and the sensitivity of detectors, to use laboratory equipment to explore structural changes upon excitation. Consequently, in this contribution we present detailed technical description of the 'in-house' X-ray diffraction setup allowing for the laser-pump X-ray-probe experiments within the time-resolution at the order of 10 μs or larger. The experimental setup consists of a modified Bruker Mo-rotating-anode diffractometer, coupled with the high-frequency Nd:YAG laser (λ = 355 nm). The required synchronization of the laser pulses and the X-ray beam is realized via the optical chopper mounted across the beam-path. Chopper and laser capabilities enable high-repetition-rate experiments reaching up to 100 kHz. In addition, the laser shutter is being directly controlled though the original diffractometer software, allowing for collection of the data in a similar manner as done at the synchrotron (alternating light-ON & light-OFF frames). The laser beam itself is split into two allowing for improved uniform light delivery onto the crystal specimen. The designed setup was tested on the chosen set of crystals exhibiting rather long-lived excited state, such as, the Cu2Br2L2 (L = C5H4N-NMe2) complex, for which the determined lifetime is about 100 μs at 90 K. The results shall be presented. Research is funded by the National Science Foundation (CHE1213223). KNJ is supported by the Polish Ministry of Science and Higher Education through the "Mobility Plus" program.
On the assessment of time-resolved diffraction results
Authors: Fournier Bertrand , Coppens Philip
Published: November 2015

Dynamic-structure crystallography, and in particular photocrystallography, is a field of great interest because of its numerous applications. The field covers the studies of reactions in crystals including non-reversible reactions, phase transitions and the structure change on excitation leading to short-lifetime species. Data collected during dynamic-structure crystallography experiments require appropriate tools to perform data analysis. The relative scaling of different sets of data recurs in time-resolved pump-probe data collection in which crystals often disintegrate before a full set of data can be collected. We discuss relative scaling and its use with the Ratio method [1], in which ratios of observed intensities collected with and without light-exposure are used as observables. The scaling method has been developed specifically for pump-probe Laue data, but is not limited to polychromatic data sets. The visualization of the externally induced structure changes in the crystal environment is of importance to check the presence of a structural response (see Fig. a) and hence to define a starting point for the structure refinement. For this purpose, ratio-based Fourier difference maps have been defined. After the structure refinement using the software LASER [2], the quality of the light-exposed structure model can be checked in direct space by visualizing the ratio-based Fourier residual maps, and, in a complementary manner, in reciprocal space by performing statistical analysis on the least-squares (LS) residual vector components with respect to the corresponding H-vectors (see Fig. b). The latter allows detection of any outliers or unexpected tendencies such as dependence of the residual vector components on the resolution or the angular direction in the reciprocal space. Application to the complex [Cu(I)-(1,10-phenanthroline-N,N′)bis(triphenylphosphine)][BF4] will be presented [3]. Research supported by the National Science Foundation (CHE1213223).
Symmetry, Aperiodicity and Ultrafast Photo-Switching in Spin-Crossover Compounds
Authors: Collet Eric , Lorenc Maciej , Cammarata Marco , Servol Marina , Cailleau Herve , Buron Marylise
Published: November 2015

The optical control of materials and related physical properties (electronic state, magnetic, optical...) by laser irradiation has gained tremendous interest within the emerging field of photoinduced phase transitions. Light-induced changes of molecular systems involve subtle coupling between the electronic and structural degrees of freedom, which are essential to stabilize the photo-excited state, different in nature from the stable state. Therefore the new experimental field of photocrystallography plays a key role. Its outreach goes far beyond simple structural analysis under laser excitation. By playing on different physical parameters and developing the techniques and analysis, one can investigate new out of equilibrium physics through light-driven cooperative dynamics and transformations in materials, or follow a chemical reaction in real time [1]. The use of photo-crystallography allows to investigate the nature, the mechanisms and the dynamics of photoinduced phase transitions. Here we will present photocrystallography studies of the photo-switching process in spin-crossover materials. On the one hand, ultrafast diffraction allows to follow the structural dynamics [2] and to probe the different processes following femtosecond laser excitation. Recent studies performed on the LCLS X-FEL have shown that the structural molecular changes, with the characteristic Fe-N bond elongation, occur within 160 fs. On the other hand, we will present investigations on the effect of light excitation on spin-state concentration waves, which may be of aperiodic nature (Figure, [3]). Time-resolved x-ray diffraction studies reveal that the high symmetry phase is reached only after milliseconds.
Fleeting Excited States by Synchrotron and In-House Pump-Probe Diffraction
Authors: Coppens Philip
Published: November 2015

While the geometry of the initial state of chemical reactions is now being studied by electron diffraction methods [1] with further efforts underway at XFEL's, the properties of longer lived molecular excited states remain of crucial importance for the design of photoluminescent devices [2] and as precursors in photochemical reactions and electron transfer into semiconductor nanoparticles. Triplet lifetimes in crystals are temperature dependent, but typical in the ns-ms range. If high luminescence is of importance, the lower part of this range is preferable, for other applications longer lifetimes may be desirable. In the former case time-resolved (TR) synchrotron experimentation, preferable with Laue techniques, is the method of choice, whereas for lifetimes above about 10 µs monochromatic in-house TR methods are increasingly feasible due to the continuing increase in the brightness of commercial X-ray sources and in the efficiency of detectors. The in-house method implemented in our laboratory uses a fast mechanical shutter synchronized with up to 100 kHz high repetition-rate lasers, corresponding to a pulse separation of 10 µs, as discussed in detail in a presentation by Kaminski. A number of synchrotron [3] and in-house experiments on mono- bi- and tetra-nuclear organometallic complexes have been completed and are compared. New methods for inter-sample scaling of multi-sample data sets and for visualization of the geometrical changes increase the sensitivity of the TR methods and allow examination of geometry changes on excitation at conversion percentages of only a few %. Further details will be presented in separate presentations. Research funded by the National Science Foundation (CHE1213223). BioCARS Sector 14 at APS is supported by NIH (RR007707). The Advanced Photon Source is funded by the Office of Basic Energy Sciences, U.S. Department of Energy, (W-31-109-ENG-38).
Capturing structural dynamics of materials by picosecond X-ray pulses
Authors: Adachi Shin-ichi , Sato Tokushi , Nozawa Shunsuke
Published: November 2015

Picosecond time-resolved X-ray techniques, such as time-resolved X-ray diffraction, scattering, and spectroscopy, utilize the pulsed nature of synchrotron radiation from storage rings, and are becoming general and powerful tools to explore structural dynamics in various materials. This method enables to produce "atomic structural movies" at picosecond temporal resolution. It will be fascinating to apply such capability to capture ultrafast structural dynamics in advanced materials of strongly-correlated electron systems, photochemical catalytic reaction dynamics in liquid or on solid surface, light-induced response of photosensitive proteins, etc. Photon Factory Advanced Ring (PF-AR) at the High Energy Accelerator Research Organization (KEK), Tsukuba, Japan is a 6.5-GeV electron storage ring dedicated for single-bunch operation and is suitable for the picosecond time-resolved X-ray studies. An in-vacuum undulator beamline NW14A at the PF-AR was designed and constructed to conduct a wide variety of time-resolved X-ray measurements, such as time-resolved X-ray diffraction, scattering and spectroscopy [1]. Successful examples of time-resolved X-ray studies applied to materials science will be presented in the talk.
High-pressure synthesis and physical properties of A-site ordered perovskites
Authors: Long Youwen
Published: November 2015

ABO3-type perovskite oxides exhibit a wide variety of interesting physical properties such as superconductivity, colossal magnetoresistance, multiferroic behavior etc. For a simple ABO3 perovskite, if three quarters of the A site is replaced by a transition metal A', then the so-called A-site ordered double perovskite with the chemical formula of AA'3B4O12 can form. Since both A' and B sites accommodate transition metal ions, in addition to conventional B-B interaction, the new A'-A' and/or A'-B interaction is possible to show up, giving rise to the presence of many novel physical properties. Here we will show our recent research work on the high-pressure synthesis of several A-site ordered perovskites as well as a series of interesting physical properties like temperature- and pressure-induced intermetallic charge transfer, negative thermal expansion, magnetoelectric coupling multiferroic and so on. [1-3]
Synthesis of α-cristobalite-type CO2-SiO2under extreme conditions
Authors: Haines Julien , Santoro Mario , Gorelli Federico , Bini Roberto , Cambon Olivier , Levelut Claire , Salamat Ashkan , Garbarino Gaston
Published: November 2015

Extreme conditions change the behavior and reactivity of elements and compounds and permit the synthesis of novel materials. In the case of group IV oxides, molecular CO2and a network solid silica, which were considered to be incompatible, are found to react under HP-HT conditions. A crystalline CO2-SiO2solid solution was synthesized from molecular CO2and microporous silicalite SiO2at 16-22 GPa and temperatures above 4000 K in a laser heated diamond anvil cell [1]. Synchrotron X-ray diffraction data show that the crystal adopts a densely packed α-cristobalite structure (space group P41212) with carbon and silicon in 4-fold coordination. This occurs at pressures at which SiO2normally adopts a 6-fold coordinated rutile-type stishovite structure. The P-T conditions used in this study represent a compromise between the respective stabilities of 3- and 4-fold coordination in CO2and 4- and 6-fold coordination in SiO2. This solid solution can be recovered at ambient pressure at which the unit cell volume is 26% lower than that of α-cristobalite SiO2. This is due to the incorporation of much smaller carbon atoms, resulting in the collapse of the oxygen sublattice. The unit cell volume and the different C and Si sites identified in Raman spectroscopy are consistent with a C:Si ratio of 6(1):4(1). The tetragonal c/a ratio increases from 1.283 at 16 GPa to 1.303 at ambient pressure and is lower than that of SiO2due to the more compact structure of the new material and essentially corresponds to that of the dense rutile-type oxygen sublattice. This can explain the small variation in volume observed for this phase corresponding to a bulk modulus of about 240 GPa. Due to the incorporation of silicon atoms, this hard solid based on CO4tetrahedra can be retained as a metastable phase. This strongly modifies standard oxide chemistry and shows that carbon can enter silica giving rise to a new class of hard, light, carbon-rich oxide materials with novel physical properties.
TEM observation for low-temperature grown spinel-type LiMn2O4crystals
Authors: Yubuta Kunio , Mizuno Yusuke , Zettsu Nobuyuki , Komine Shigeki , Kami Kenichiro , Wagata Hajime , Oishi Shuji , Teshima Katsuya
Published: November 2015

Present spinel-type lithium manganese oxides have attracted much attention as positive-electrode active materials for lithium-ion rechargeable batteries, which are the most sought-after power source for various electric applications, because of their low cost, non-toxicity, and high abundance of source materials compared to the conventionally used LiCoO2 crystals. Spinel-type LiMn2O4 crystals were grown at low-temperature by using a LiCl-KCl flux. The chemical compositions, sizes, and shapes of the LiMn2O4 crystals could be tuned by simply changing the growth conditions. Among the various products, the crystals grown at a low temperature of 873 K showed a small average size of 200 nm. Electron diffraction patterns and TEM images reveal the truncated octahedral shape of the crystals. The flux growth driven by rapid cooling resulted in truncated octahedral LiMn2O4 crystals surrounded by both dominating {111} and minor {100} faces with {311} and {220} edges. Lattice images indicate that crystals grown at a lower temperature have the excellent crystallinity. The small LiMn2O4 crystals grown at 873 K showed better rate properties than the large crystals grown at 1173 K, when used as a positive active material in lithium-ion rechargeable batteries.
Valence Electron Distributions in Ferroelectric Barium Titanate Nanopowders
Authors: Kuroiwa Yoshihiro , Yamada Masashi , Magome Eisuke , Moriyoshi Chikako , Tanaka Hiroshi , Wada Satoshi
Published: November 2015

Barium titanate BaTiO3 is one of the most important perovskite-type electroceramics, which undergoes the phase transition at 1300C from cubic to tetragonal, and exhibits ferroelectricity at room temperature. The phase transition depends on the particle size. BaTiO3 powders with the particle sizes less than several tens of nanometers are known to show no phase transition and hence no ferroelectricity at room temperature. The size effect of BaTiO3 is the most important issue in designing small ceramic capacitors with high capacitance. Our group has been devoted to visualizing the electron density distributions of perovskite-type oxides by analyzing the synchrotron-radiation x-ray powder diffraction (SXRD) data measured at SPring-8 using the maximum entropy method (MEM)/Rietveld method [1, 2]. In this study, the distributions of valence electrons in the outer shells of atoms are derived accurately from the SXRD data of BaTiO3 nanopowders to prove the characteristic chemical bondings which govern the ferroelectric phase transition. The powder samples used were 500 and 35 nm in particle sizes. The former showed the phase transition whereas the latter showed no phase transition. The MEM valence electron density studies at 2000C in the cubic structure revealed the clear structural variations that the Ti-O covalent bonding is found in the 500 nm sample, while all the valence electrons are localized at the O sites in the 35 nm sample exactly like an ionic crystal. Ferroelectricity originates from the balance between the long-rage Coulomb force and the short-range repulsion force. The obtained results provide direct experimental evidence that the electron orbitals hybridization on the Ti-O bonds weakens the short-range repulsion force, and causes the second-order Jahn-Teller distortion on the TiO6 octahedron in the 500 nm sample. We consider that the Ti-O bonding in the prototype structure governs the ferroelectric phase transition temperature in BaTiO3.
Morphology Controlled Lifetime and Selectivity in Zeolite Catalysis
Authors: Teketel Shewangizaw , Lundegaard Lars , Skistad Wegard , Olsbye Unni , Lillerud Karl Petter , Beato Pablo , Svelle Stian
Published: November 2015

Zeolites are widely used in the chemical industry for their catalytic properties and their ability to control the size and shape of both reactant and product molecules. In this presentation we will show unexpected catalytic properties of ZSM-57 and SUZ-4 during conversion of methanol to hydrocarbons (MTH). We have previously shown how analysis of anisotropic peak broadening in XRPD data [1] can reveal not only the average shape of the crystallites, but also how the zeolite channels are orientated relative to the morphology [2]. The same method was used to analyze the ZSM-57 and SUZ-4 samples revealing nano-sheet and -needle morphologies respectively. Electron imaging and diffraction furthermore revealed that the sheets of ZSM-57 are five-fold twinned with the 10-ring channel system perpendicular to the sheet. The 8-ring channel system would form a closed pentagon shape in defect free crystals. Based on these observations we will explain the remarkable MTH lifetime and selectivity displayed by the ZSM-57 and SUZ-4 samples respectively [3].
Neutron diffraction strain mapping in engineering materials
Authors: Payzant Edward , Sochalski-Kolbus Lindsay
Published: November 2015

Bragg peak positions with precisions of a few parts in 10^4 are typically necessary to provide the strain resolution required for measurement of the residual strains in bulk materials. Neutron diffraction, mainly because of its high penetration in many engineering materials, provides a unique non-destructive capability for strain measurement. Dedicated instruments for mapping lattice strains using neutron diffraction, a technique first demonstrated in the 1980s, are found at all major neutron scattering facilities around the world. Residual stresses typically arise during synthesis, forming, joining, thermal processing, or use of engineering materials and can significantly impact the strength and performance of the final part. We present two recent examples of strain-mapping experiments conducted at the HB-2B beamline at the High Flux Isotope Reactor. Strain-mapping data collected on a friction stir welded ODS alloy reveals changes in texture and stress resulting from the FSW process, and dependent on the FSW process variables. Mapping experiments on steel conduit intended for the ITER project show the strain distribution from the forming operations, and the partial reduction of these strains through high temperature annealing.
The impact of zinc on insulin fibrillation
Authors: Frankaer Christian , Blanner Maria , Groenning Minna , Bukrinski Jens , Harris Pernille
Published: November 2015

Protein and peptide amyloid fibrillation is an increasingly significant field of research due to the growing prevalence and recognition of amyloid-related human diseases and in relation to therapeutic applications of peptide drugs where it constitutes a challenge during production and transportation. Insulin fibrillation represents a good model system for fibrillation studies and numerous pathways of insulin fibrillation have been suggested [1]. In general, partially unfolded insulin monomers (or dimers) are believed to be a vital prerequisite for prefibrillar association and eventually fibril formation (reviewed by Groenning in [1]). As fibrillation is commonly found to occur from the biologically active, monomeric form of insulin, zinc is considered to impede insulin fibril formation through stabilization of the physiological predominant hexameric forms. The question arises whether the assigned monomeric pathway at least to some degree could be a premise generated from the usual experimental procedure of inducing fibril formation; experiments that are conducted at acidic conditions with protonated histidine residues that cannot coordinate the Zn(II) ions, to induce the monomeric form believed to be the prerequisite of insulin fibrillation? However, in a more recent study [2], it was suggested that Zn(II) ions in contrast also inhibit fibrillation through differential stabilization of the insulin monomer. In the present work, we have investigated the presence and influence of zinc at well-defined stoichiometric levels at physiological pH, as well as the inner coordination sphere of Zn(II) during insulin fibril formation, using X-ray absorption spectroscopy (XAS). In addition, the results were validated with fiber diffraction studies, small-angle X-ray studies and ThT fluorescence studies.
Multi-probe methods for investigating ion hydration
Authors: Diaz-Moreno Sofia , Bowron Daniel
Published: November 2015

Techniques developed at large scale facilities such as X-ray synchrotrons and pulsed or reactor based neutron sources have, over the past few decades, played a significant role in unravelling many of the mysteries that underpin the chemical, physical and biochemical properties of ions in solutions. In this presentation we will illustrate how the combination of X-ray diffraction, neutron diffraction and X-ray absorption spectroscopy can be applied to the investigation of the structure of ion hydration shells. Examples of hydration of di- and tri-valent ions will be shown. In particular we will present an investigation of the hydration structure of copper (II) ions using this multi-technique approach, and discuss the findings in the context of biological and chemical systems.
The inhibitory mechanism analysis of human chymase specific inhibitor TJK002
Authors: Takimoto-Kamimura Midori , Kakuda Shinji , Matsumoto Yoshiyuki
Published: November 2015

Chymase is a mast cell specific serine protease that is stored within secretory granules and released together with heparin and histamine in response to allergen challenge or other stimuli. Recent study have shown that chymase possess processing activity for biological peptides and cytokines implicated in a variety of diseases. For example, the chymases of primateds and dogs have highly specific angiotensin II generating activity, and the results of animal studies suggest the chymase contributes to the pathogenesis of cardiovascular diseases via Ang II generation. Based on the results of these studies, inhibition of chymase is expected to provide therapeutic means for the treatment of these diseases. Recently, we have developed some novel benzimidazole derived in human chymase inhibitors and the crystal structure of human chymase complexed with a nobel benzimidazole inhibitor TJK002 was obtained at 2.8A. TJK002 showed potent inhibitory activity (Ki value 2.24nM) with respect to human chymase. X-ray crystallographic structure showed that THK002 forms an anon-covalent interaction with the catalytic domain of human chymase. 4-methylbenzothiophen-3-yl moiety of TJK002 occupies the S1 pocket. The carboxylic acid for hydrogen bonds with the imidazole N (e) atom of H57 and O (g) atoms of Ser195 at the catalytic site. The binding mode of TJK002 is very unique and attractive compared other cymase inhibitors. It depends on the binding mode of TJK002 and reflects to its biological function. Because by site-directed mutagenesis, human mast cell chymase are responsible for an acidic amino acid residue preference in the P2' position of substrates. Chymase inhibitors besides TJK002 have negatively charged p2' moiety. But TJK002 doesn't have such a moiety which binds to S2' site, but it still has a strong incisory activity. We clarify its strong inhibitory mechanism of TJK002 by Fragment molecular orbital (FMO) calculation. We discovered the stacking interaction between the benzimidazole ring and His57 is quite effective for the inhibitory activity of TJK002.
Fragment-screening at the BESSY II MX-beamlines of the Helmholtz-Zentrum Berlin
Authors: Mueller Uwe , Ühlein Monika , Linnik Janina , Heine Andreas , Klebe Gerhard , Weiss Manfred
Published: November 2015

"Within the last decade, the fragment-based screening approach has been matured to a reliable and powerful instrument of pharmaceutical drug discovery. The success of fragment screening strongly depends on the quality of the chosen fragment library (100-200 Da), the quality of the target protein diffraction as well as the possibility to use high throughput methods for the screen application. A thorough crystallographic analysis of many protein-fragment complex structures and their binding modes has the perspective to result in the development of new potential lead structures and to map the interaction landscape of protein surfaces. Recently we started the development of a dedicated experimental facility for high throughput fragment screening at the BESSY II storage ring. The in house data processing pipeline ""XDSAPP"" [1] has been developed to speed up the data evaluation of large amounts of diffraction data. We have assembled a fragment library of 96 compounds and have validated this library against two target proteins. These first results suggest that our library is capable of identifying binding partners at a hit rate of close to 10%. This library together with a fully automated beam line [2] will be made accessible to users, thus enabling fragment-screening experiments on a much broader basis. "
X-ray structures of Aldose Reductase and AKR1B10 with the lead inhibitor JF0064
Authors: Ruiz Francesc Xavier , Cousido-Siah Alexandra , Mitschler André , Porté Sergio , de la Fuente Jesús , Terwesten Felix , Klebe Gerhard , Farrés Jaume , Parés Xavier , Podjarny Alberto
Published: November 2015

Human enzymes Aldose Reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications and inflammatory disorders (AR) and in several type of cancers, e.g. hepatocellular carcinoma and smoking related lung cancer (AKR1B10). They belong to the Aldo-keto reductase family (AKRs) which present a highly conserved (α/β)8 barrel folding. Their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. JF0064 (2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol) has been identified in a series of polyhalogenated compounds as a lead inhibitor of both enzymes. The determination of the X-ray structure of the AR:NADP+:JF0064 complex at ultrahigh-resolution (0.85 Å) allows to observe JF0064 interacting with the catalytic residue Tyr48 through a negatively charged hydroxyl group of the inhibitor (i.e., the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group will also be present in the case of AKR1B10. The X-ray structure of the AKR1B10:NADP+:JF0064 complex (achieved with the combination of surface lysine methylation and the introduction of K125R/V301L mutations) and the comparison between both structures unveils some important hints for a structure-based drug design optimization.
Native Hexameric Full-Length HIV-1 Capsid: Crystal Structure and Drug Targeting
Authors: Gres Anna , Kirby Karen , Hachiya Atsuko , Michailidis Eleftherios , Pornillos Owen , Sugiura Wataru , Lee KyeongEun , KewalRamani Vineet , Tanner John , Sarafianos Stefan
Published: November 2015

The HIV-1 full length capsid protein (CA-FL) is increasingly viewed as an attractive therapeutic target since proper capsid formation is required for viral infection. CA-FL is synthesized as a central domain of a structural Gag polyprotein that is involved in both early and late stages of the viral life cycle. During the HIV-1 maturation process, Gag is cleaved by a viral protease to produce several discrete new proteins that include matrix, capsid (CA-FL), and nucleocapsid. After proteolytic cleavage, CA-FL forms hexamers and pentamers that rearrange into a fullerene cone-shaped structure, which surrounds the viral genome at the center of the mature virus. Crystal structures of the native unassembled hexameric CA-FL (without cross-linked residues that might prevent changes in the inter- or intra-subunit interactions) are of great interest, as they may provide insights relevant to the development of drugs that prevent or impede the transition from the preassembled to the assembled capsid states. Recently, we crystallized and solved the crystal structure of the first hexameric HIV-1 CA-FL in its native form (without engineered cross-linking cysteines). There is one molecule per asymmetric unit, and the P6 space group generates the native hexameric assembly. We have also identified a small molecule, 18E8, which exhibits broad anti-HIV activity in cell-based assays, and targets CA-FL. This was demonstrated by experiments that selected for viruses with drug resistance and revealed that an A105T mutation in CA-FL confers resistance to the compound. Time-of-inhibitor addition experiments showed that 18E8 targets an early step in the HIV replication cycle, after reverse transcription and before integration. Electron microscopy experiments suggest that 18E8 does not impart significant morphological changes in CA-FL tubular assemblies. Our structure of CA-FL and our ongoing work with the CA-FL/18E8 complex will provide a system for the investigation of molecular interactions between CA-FL and small molecule antivirals that work with a novel mechanism of action.
24 hours – High-Throughput Crystal Structure Production
Authors: Wagner Trixie , Kroemer Markus , Grunwald Berthold
Published: November 2015

In the pharmaceutical industry crystal structures of low molecular weight compounds are analyzed for a variety of reasons: absolute structure determination, proof of constitution, characterization of different polymorphic forms, obtaining three-dimensional models as starting points for the study of structure-activity relationships, etc. Not for all purposes highly redundant, high-resolution data sets are needed; this thought, together with the purchase of a new hybrid pixel detector which can be operated in a very fast shutterless mode, initiated the idea to test how many useable crystal structures we can produce within 24 hours. Our goal was to invest as little effort as possible and to set up an automated process with minimal human intervention but a maximum chance of success which we defined as getting to a correct final result providing useful information, e.g., is it the correct compound? Is the sample chiral or racemic? Which crystal would be the best one for a full data collection? Is it a new polymorph? We selected a data collection protocol which yields an interpretable data set up to 1 Å resolution in less than 10 minutes, the diffraction images are indexed and processed using an in-house script arching over the necessary individual XDS steps, followed by space group determination (XPREP) and structure solution/refinement (SHELX). First results and findings of our experiment series will be presented and the adjustable parameters will be discussed. Ideas to adapt and improve the process will be offered.
Development of "Reciprocal Viewer and Analyzer" for Neutron C-2DPSD
Authors: Ishikawa Yoshihisa , Lee Chang-Hee , Kim Shin-Ae , Moon Myungkook , Noda Yukio
Published: November 2015

"A new single crystal neutron diffractometer by using a curved two-dimensional position sensitive detector (C-2DPSD) has been installed at HANARO-ST3 beam port [1]. Compared with a conventional point detector, a two-dimensional detector has huge reciprocal space information in general. It has advantages to detect superlattice peaks and diffuse scattering etc. without any pre-information. In order to obtain significant diffraction intensity in the reciprocal space, it is essential the efficient program for handling the measuring data directly. In these several years, we have developed the methodology and the program package "Reciprocal Analyzer", based on many experiments by the C-2DPSD, which includes peak search [2], UB matrix determination, and quantitative assessment of the accurate integrated intensities [3]. And to visualize reciprocal space from raw pixel data of the C-2DPSD, the ""Reciprocal Viewer"" has been developed also. These software are coded by C/C++ and Python with OpenGL as a cross-platform GUI. Figures show the graphical interface of Recipocal Analyzer and Viewer. Details of the feature about these software will be introduced at the presentation."
CMOS – Shutterless Operation Boosts Speed and Quality
Authors: Adam Martin , Hovestreydt Eric , Ott Holger , Noll Bruce , Ruf Michael
Published: November 2015

CMOS technology based X-ray detectors offer numerous advantages compared to traditionally used CCD detectors: · CMOS sensors are available in larger sizes with a pixel size optimized for X-ray scattering and X-ray diffraction. · CMOS sensors have lower power consumption than CCDs and provide excellent signal-to-noise ratios even when only moderately cooled. This allows the design of air-cooled detectors. Both, low power consumption and no need for cooling-water, lead to minimized pre-installation requirements. · While CCDs use a bucket brigade read-out, CMOS technology does allow continuous direct sensor read-out. These features make modern CMOS based X-ray detectors, such as the PHOTON 100, an excellent solution for single crystal X-ray diffraction (SC-XRD) experiments. In particular, the capability to continually read out pixels provides a new approach for data collection. While CCDs require closing the shutter for each read-out step, introducing system overhead, CMOS based detectors can be operated in shutterless mode, which not only eliminates over-head time but it also reduces mechanical jitter. We will present details on the implementation of shutterless readout in the current state-of-the-art SC-XRD instrumentation, the D8 QUEST and D8 VENTURE systems. Furthermore, the impact of shutterless read-out on data quality and data collection speed will be discussed using examples from chemical crystallography and structural biology.
Mono- & ditrityl ethers, amines & amides – a family of multifaceted materials
Authors: Rychlewska Urszula , Bendzinska-Berus Wioletta , Janiak Agnieszka , Warzajtis Beata
Published: November 2015

In the course of our recent study on the possible transfer of chirality from the stereogenic center(s) to the inherently helical triphenylmethyl (Tr) substituent we have structurally characterized mono- and ditrityl derivatives of chiral alcohols, amines and amides. During the course of our investigations we have experienced various kinds of packing peculiarities caused by the presence of sterically demanding chiral molecules, e.g. quasi-isomorphism between a pair of enantiomerically pure and racemic crystals, microporosity, lattice inclusion, multiplication of asymmetric units and pseudosymmetry. The total absence of classical amide...amide hydrogen bonding and rare involvement of amine hydrogen in intermolecular hydrogen bonding opens the door to intra- and intermolecular interactions involving π-electron systems and points to the dispersion energy as the crystal structure determining factor, despite a common believe that the intermolecular hydrogen bonds are the crucial determinants of crystal packing.
Towards computer-guided tuning of the crystal packing of porous organic cages
Authors: Pulido Angeles , Liu Ming , Reiss Paul , Slater Anna , Chong Sam , Little Marc , Hasell Tom , Briggs Mike , Cooper Andrew , Day Graeme
Published: November 2015

Among microporous materials, there has been an increasing recent interest in porous organic cage (POC) crystals, which can display permanent intrinsic (molecular) and extrinsic (crystal network) porosity. These materials can be used as molecular sieves for gas separation and potential applications as enzyme mimics have been suggested since they exhibit structural response toward guest molecules[1]. Small structural modifications of the initial building blocks of the porous organic molecules can lead to quite different molecular assembly[1]. Moreover, the crystal packing of POCs is based on weak molecular interactions and is less predictable that other porous materials such as MOFs or zeolites.[2] In this contribution, we show that computational techniques -molecular conformational searches and crystal structure prediction- can be successfully used to understand POC crystal packing preferences. Computational results will be presented for a series of closely related tetrahedral imine- and amine-linked porous molecules, formed by [4+6] condensation of aromatic aldehydes and cyclohexyl linked diamines. While the basic cage is known to have one strongly preferred crystal structure, the presence of small alkyl groups on the POC modifies its crystal packing preferences, leading to extensive polymorphism. Calculations were able to successfully identify these trends as well as to predict the structures obtained experimentally, demonstrating the potential for computational pre-screening in the design of POCs within targeted crystal structures. Moreover, the need of accurate molecular (ab initio calculations) and crystal (based on atom-atom potential lattice energy minimization) modelling for computer-guided crystal engineering will be discussed.
Halogen- versus Hydrogen-Bonds Aggregation and Competition at High Pressure
Authors: Podsiadło Marcin , Katrusiak Andrzej
Published: November 2015

Halogen and hydrogen bonds [1] are most often associated with the structure of molecular crystals. Even weak specific interactions, such as halogen···halogen and CH···halogen contacts, can compete between themselves and with Kitaigorodski's close packing rule. The competition between halogen···halogen and CH···halogen interactions has been studied at high pressure for the series of six dihalomethanes CH2XY (X,Y = Cl, Br, I). They crystallize in several structural types of space groups Pbcn, C2/c, Pnma, Pna21or Fmm2. In all these compounds and in their polymorphs the halogen···halogen and CH···halogen interactions persist despite considerable structural differences. The group of monohalomethanes (CH3X, X = Cl, Br, I) are the simplest organic polar compounds and ideal models for studying halogen···halogen and CH···halogen interactions. For these simplest haloalkanes, the halogen···halogen competition with CH···halogen bonds, scaled in the function of electrostatic potential in the Cl, Br, I series, is affected by pressure. Phase α-CH3Br, isostructural with CH3I (orthorhombic space group Pnma) and dominated by halogen···halogen bonds, is destabilized by pressure. At 1.5 GPa the ambient-pressure α-CH3Br phase transforms into phase β-CH3Br governed by CH···halogen interactions. Phase β of CH3Br is isostructural with CH3Cl, orthorhombic space group Cmc21[2,3]. The CH3Br molecules are more evenly accommodated in space group Cmc21and CH···halogen interactions are favoured by the close-packing effect.
Anisotropic crystal growth of carbamazepine form I and a hydroxysulfonamide
Authors: Walshe Nicole , Erxleben Andrea , McArdle Patrick
Published: November 2015

Carbamazepine form I, CBZ, and 4-hydroxy-N-phenylbenzenesulfonamide, HPS, both exhibit highly anisotropic needle-like crystal growth. CBZ has been observed to have a corresponding anisotropy in its dissolution. Using the assumption that crystal growth and dissolution have reciprocal mechanisms[1] molecular dynamics, MD, simulations of CBZ and HPS crystal dissolution have been used to examine the mechanism of the needle growth/dissolution. MD simulations of CBZ dissolution using AMBER[2] reproduce the highly anisotropic crystal dissolution. Blocks containing between 48 and 256 molecules in 50 to 90 Å3 boxes of solvent show rapid loss of molecules from the a face. Simulation of HPS crystal dissolution also shows high anisotropy however the dissolution of HPS is much slower than that of CBZ due to the presence of hydrogen bonding chains in the structure. A two unit cell molecule centroid distance matrix analysis was used to detect molecular stacking in both structures. The direction of the hydrogen bonding in HPS is normal to the direction of growth. However the relatively rapid dissolution is in the stacking direction in both crystal structures and is attributed to the higher relative energy of surface molecules at the ends of the stacks that have a higher fraction of exposed atoms. A related analysis has been applied to flat molecule structures which are stacked. [3] If flat molecule stacks can be compared to stacks of pizza boxes then the non-flat molecules described here can be compared to stacked chairs.
Phase transformations in cucurbituril host-guest complexes
Authors: Danylyuk Oksana , Kedra-Krolik Karolina , Worzakowska Marta , Osypiuk-Tomasik Joanna , Fedin Vladimir
Published: November 2015

The retention of crystallinity upon desolvation of molecular crystals is not common, as the molecules are rigidly and densely packed in the crystals and the original framework usually collapses once solvent is removed from the structure. However, in rare cases the host framework remains substantially unaffected by solvent (guest) removal yielding structure with open channels or discrete lattice voids that can show permanent porosity. [1] Furthermore, sometimes happens, the desolvation process proceeds as single-crystal to single-crystal transformation resulting in distortion and sliding of the structure, changes in conformation, coordination modes and/or space group. Here we would like to present crystallographic study and thermal analysis on the dehydration process of the crystalline supramolecular complex between macrocyclic host cucurbit[6]uril and dopamine. In the solid state the 1:1 host-guest complex assembles into hexameric tubes with water-filled interior channels. Another set of water channels is created between three neighboring tubes in the crystal lattice. The crystals of such supramolecular assembly are not stable when out from mother solution and immediately start to loose water upon exposure to air. However, despite severe cracking the crystals dried in air maintained their integrity and still gave satisfactory diffraction pattern. The X-ray analysis showed significant decrease in the unit cell volume of the partially dehydrated crystals that corresponds to the liberation of some of the water molecules from the channels. Moreover, the reorganization of dopamine guest molecules has occurred in the crystal lattice as a response to the escape of water molecules from the structure. The partial dehydration and reorganization of the supramolecular framework proceeds via a single-crystal to single-crystal mechanism.