bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel 3d-4f CoII-GdIII system with 4,5-imidazoledicarboxylate and oxalate
Authors: Vega Andrés , Cruz Carlos , Paredes-García Verónica , Spodine Evgenia , Venegas-Yazigi Diego
Published: November 2015

The challenges of designing and synthesizing new materials, the complexity of their structures, and their potential physical properties have continued to attract a great deal of interest. The combination of organic and inorganic components into the same molecular backbone has captivated many researchers, and as a consequence of the multiple choices of the components and also of the used synthetic strategies, a wide variety of advanced materials has been obtained. In many cases, an increase in structural complexity gives rise to new properties, which cannot be foreseen on the basis of the single constituting moieties. Therefore, the assembly of different components, or molecular fragments, may give rise to new materials that exhibit interesting and useful physical and chemical properties in the condensed phase.1 From a structural and synthetic point of view, the literature shows that a wide variety of polymetallic systems ranging from 0D to 3D structures have been rationally designed and synthesized by the appropriate selection of the metal centers and organic building blocks, as well as of the reaction pathways.2 In this work, we will inform the synthesis and structural characterization of a novel 3d-4f bimetallic system: {[Co(H2O)2(ImDC)Gd(ox)2(H2O)]·2H2O}n. (ImDC: 4,5-imidazoledicarboxylate; ox: oxalate). The structure displays CoII cations having an approximately octahedral environment completed by two N,O-ImDC ligands and two water molecules, while the GdIII cations displays nine coordination completed exclusively by oxygen atoms coming from a water molecule and oxalate and ImDC anions (Figure1, left). The structure defines a covalent tridimensional lattice where two water molecules by formula are trapped inside the cavities left by this arrangement (Figure1, right). Figure 1: Structural diagram for the basic bimetallic unit Co(H2O)2(ImDC)Gd(ox)2(H2O) (left) and the packing showing trapped water molecules {[Co(H2O)2(ImDC)Gd(ox)2(H2O)]·2H2O}n (right). Acknowledgements: The authors acknowledge financial support from FONDECYT 1130643, Financiamiento Basal, FB0807. C.C. thanks CONICYT Fellowship.
Data Validation and Structural Classifications in Powder Diffraction File
Authors: Kabekkodu Soorya
Published: November 2015

The new Powder Diffraction File™, housing more than 760,000 diffraction patterns and 200,000 crystal structures, has a wealth of information that a materials scientist can take advantage of in various ways, from materials identification, characterization to design. Various structural and chemical classifications implemented in the database will be presented in detail. These classifications are important in data mining studies and optimizing pattern search/match methods. While using any database in materials characterization, it is important to know the quality of the crystal structure or diffraction pattern found in the database. With varying quality of published data in the literature, database editorial review processes had to adopt rigorous data evaluation methods to classify data based on its quality. Every entry in the Powder Diffraction File™ has a quality mark and editorial comments describing the error and the correction. Results of the analysis of the quality of the crystal structures (~500,000) published over the years will be discussed along with the most common errors found. The recent developments in Powder Diffraction File will be presented.
Determination of Chirality of the Chiral Space Groups with Two-fold Screw Axis
Authors: Ishikawa Kazuhiko , Tanaka Masahito , Shiro Motoo , Asahi Toru
Published: November 2015

Crystals are classified according to their symmetry operations into 230 space groups. A two-fold screw axis, 21, a symmetry operation, is frequently found in the crystal, especially non-centrosymmetric organic crystals. The two-fold screw axis shows a chiral character when molecules in the crystal tilt against the screw axis as shown in Figure. The crystals belonging to a chiral space group with two-fold screw axis such as a P21or P212121exhibit two different types with opposite chirality. However, although the two crystals are not identical in a molecular arrangement, we cannot distinguish them with the present notation of space group. Recently, the idea of determining the handedness of two-fold screw axis have been successfully proposed using hierarchical interpretation of the crystals.(I. Hisaki, T. Sasaki et al., 2012) Nevertheless, the issue on a notation to distinguish chiral crystals with two-fold screw axis still remains unsettled as far as we know. Therefore, we attempt to propose a novel notation for the crystals belonging to chiral space groups with two-fold screw axis. We focus on the relationship between the absolute structure and optical activity of the crystals. We have selected alanine crystals, which belong to P212121, as model crystals to discuss the notation. We have determined the absolute structure of the alanine crystals by X-ray diffraction and have measured their optical activity with Generalized High Accuracy Universal Polarimeter (G-HAUP).(M. Tanaka, N. Nakamura et al., 2012) G-HAUP is an apparatus that can measure simultaneously the linear birefringence, linear dichroism, circular birefringence, i.e., optical activity, and circular dichroism in any solid material. These experimental results have successfully correlated the absolute structure to the optical activity of the alanine crystals.
Structural Characterization of Iron(iii) Dinuclear Complexes
Authors: Fuentealba Mauricio , Gonzalez Deborah , Artigas Vania
Published: November 2015

Dinuclear complexes have been studied for different purposes: magnetic materials[1], Non-linear optics materials[2], molecular switches [3], mixed-valence systems, etc. With these antecedents in mind, we present in this work a new series of dinuclear Iron(III) complexes formed by different Schiff bases ligands. The reaction starting from the iron chloride salts with the 5-chloro or 5-bromo-salycilaldehyde and ethylendiamine yields two different kinds of dinuclear iron complexes in different reaction conditions. The first one (Fig N°1), are methoxo-bridged dinuclear iron(III) complexes in which each metal centre is coordinated with one mono-condensated Schiff base ligand, one 4-chloro or 4-bromo-2-(dimethoxymethyl)phenoxo ligand and two bridging methoxo ligands. The iron(III) centres are hexacoordinated (FeN2O4), the coordination sphere is formed by 2 nitrogen atoms of the ethylendiamine fragment, 2 oxygen atoms from the hydroxyl of the Schiff base and two O atoms from the methoxo ligands. Both iron(III) centres are related by a inversion centre. The second one (Fig N°2), the dinuclear complex is formed for the double condensation of ethylendiamine with 5-chloro or 5-bromo-salycilaldehyde and one oxygen from the dianionic ligand act as bridge with another unit. The iron (III) centres are also hexaccordinated (FeN2O3Cl) formed by 2 nitrogen atoms from ethylendiamine fragment and 3 oxygen atoms from hydroxyl from Schiff base ligands and one chloro ligand. Finally, the electronic and redox properties have been studied by UV-Visible and cyclic voltammetry. ACKNOWLEDGMENT FONDECYT N01130640, FONDEQUIP EQM120095 and Beca CONICYT folio 21130944
Identification of Catalytic Residues in ATP-Citrate Lyase
Authors: Singh Noreen , Holoweckyj Kelsey , Fraser Marie
Published: November 2015

An enzyme in the human body that regulates lipogenesis and cholesterolgenesis is ATP-citrate lyase (ACLY) [1]. ACLY synthesizes acetyl-CoA and oxaloacetate from citrate, CoA and ATP, with citryl-CoA as an intermediate [1]. The product acetyl-CoA is involved in cell growth as well as embryonic and brain development [1]. Studies in mice suggest that ACLY is important during brain development as homozygous Acly knockout mouse embryos died early in development [2]. Knowledge of the reaction mechanism is limited and will be of use in understanding the energy flow in cells. Our current insight into the mechanism by which citryl-CoA is cleaved to form acetyl-CoA and oxaloacetate is based on sequence similarity of ACLY to citrate synthase (CS). Both enzymes have histidine and aspartic acid residues at similar positions in their sequences. We hypothesize that citryl-CoA binds at this site in ACLY and is cleaved into acetyl-CoA and oxaloacetate using these residues. To test this hypothesis, we have mutated these residues to alanine in both human ACLY and ACLY from the bacterium, Chlorobium limicola. Enzymatic activities of the mutant proteins were tested using a coupled-enzyme assay with malate dehydrogenase. The inactive mutants are being used in crystallization trials with substrates, since complexes of the intermediate citryl-CoA can be trapped on the protein. To date, the crystal structure of full-length ACLY has not been published. The structure of only the amino-terminal two-thirds of the human enzyme has been determined [3]; however, the part of the protein that is similar to CS is the carboxy-terminal portion. This work identifies the catalytic residues of ACLY and complements the previous structure determination, increasing our currently limited knowledge about this enzyme.
Orange Fluorescent Proteins: Filling the Spectral Gap
Authors: Pletnev Sergei , Shcherbakova Daria , Subach Oksana , Malashkevich Vladimir , Almo Steven , Dauter Zbigniew , Verkhusha Vladislav
Published: November 2015

Fluorescent proteins (FPs) have become valuable tools for molecular biology, biochemistry, medicine, and cancer research. Starting from parent green fluorescent protein (GFP), most challenging task of the FPs studies was the development of FPs with longer excitation/emission wavelength. This pursuit was motivated by advantages of so-called red-shifted FPs, namely, lower background of cellular autofluorescence in microscopy, lower light scattering and reduced tissue absorbance of longer wavelengths for in vivo imaging. In addition to FPs with regular spectral properties, there are proteins of other types available, including FPs with a large Stokes shift and photoconvertible FPs. These special kinds of FPs have become useful in super-resolution microscopy, imaging of enzyme activities, protein-protein interactions, photolabeling, and in vivo imaging. According to their emission wavelength, red-shifted FPs could be divided in the following groups: 520-540 nm yellow FPs (YFPs), 540-570 nm orange FPs (OFPs), 570-620 nm red FPs (RFPs), and > 620 nm far-RFPs. Red shift of the excitation/emission bands of these FPs is predominantly achieved by extension of the conjugated system of the chromophore and its protonation/deprotonation. The variety of spectral properties of FPs (excitation and emission wavelength, quantum yield, brightness, photo- and pH- stability, photoconversion, large Stokes shift, etc) results from the different chromophore structures and its interactions with surrounding amino acid residues. In this work we focus on structural studies and molecular mechanisms of FPs with orange emission.
Structure and dynamics of the DBHS protein family members SFPQ, NONO and PSPC1
Authors: Knott Gavin , Lee Mihwa , Passon Daniel , Sadowska Agata , Fox Archa , Conte Maria , Bond Charles
Published: November 2015

The Drosophila behaviour/human splicing (DBHS) proteins are a family of obligatory dimeric proteins found in higher order mammals down to the simplest invertebrates. `Multifunctional protein family' essentially captures what is understood regarding DBHS protein function where they are cited to regulate transcriptional initiation, the processing and export of RNA, maintenance of genomic DNA, nuclear pH homeostasis and carcinogenesis [1]. Furthermore, with roles in binding a diverse range of RNAs and both single and double stranded DNA, it is difficult to establish a coherent picture for their nuclear activities. In humans, the family consists of three highly conserved members, namely Non-POU domain-containing octamer-binding protein (NONO/p54nrb), splicing factor proline/glutamine rich (SFPQ/PSF) and paraspeckle protein component 1 (PSPC1). The conserved DBHS region of these proteins comprises tandem RNA recognition motifs (RRMs), a NOPS domain and a C-terminal coiled-coil domain. The unique structural arrangement of these domains facilitates an intimate dimerisation interface that gives rise to a novel arrangement of RRMs [2]. Given this interface, it is not surprising that DBHS proteins likely exist as either homo- or heterodimers in vivo. Here we report the first structure of the ancestral C. elegans DBHS protein, NONO-1, refined to 2.8 Å. The structure clearly illustrates the consistent obligatory nature of DBHS dimerisation and through isothermal titration calorimetry we have demonstrated that human DBHS proteins prefer a heterodimeric state in vitro. There is a growing appreciation for the fundamental significance of DBHS proteins in human health and disease and this work highlights the critical need for a more robust assessment of in vivo DBHS function.
Structure of STM3169, a tripartite ATP-independent periplasmic transporter
Authors: Jang Jun Young , Suh Se Won
Published: November 2015

Substrate-binding proteins (SBPs) form a group of proteins that are commonly related to membrane protein complexes for transport or cell signal transduction. SBPs are comprised of prokaryotic ATP-binding cassette (ABC)-transporters, prokaryotic tripartite ATP-independent periplasmic (TRAP)-transporters, prokaryotic two-component regulatory systems, eukaryotic guanylatecyclase-atrial natriuretic peptide receptors, G-protein coupled receptors (GPCRs) and ligand-gated ion channels (Berntsson et al., 2010).The TRAP transporters are less known as compared with ABC transporters but are ubiquitous in prokaryotes. The TRAP transporters are important elements of solute uptake systems in prokaryotes. These transporters contain two membrane protein components, predicted to have four and twelve transmembrane helices, respectively. In the TRAP transporters of DctP-type, substrate recognition is mediated through a well-conserved and specific arginine/carboxylate interaction in the SBP (Mulligan et al., 2011). Here we have determined the crystal structure of the TRAP transporter from Salmonella entericaserovarTyphimurium. Unexpectedly, this structure shows that various ligands can bind to the TRAP transporters. It provides insights into substrate binding mechanism in the TRAP transporter system.
Structure/Function studies on Glucan Binding Protein C of Streptococcus mutans
Authors: Purushotham Sangeetha , Larson Matthew , Banas Jeffrey , Deivanayagam Champion
Published: November 2015

Streptococcus mutans is a known etiological agent in dental caries. In the past several years, we have taken a concerted effort toward understanding the adhesion mechanisms adopted by the surface proteins S. mutans. The Glucan Binding Protein C (GBPC) is a LPXTG anchored surface protein on S. mutans that has been widely implicated to play a significant role in biofilm formation. GBPC displays limited homology to the V-region of Antigen I/II (AgI/II), another surface protein of S. mutans (1,2). We undertook to crystallize and resolve the structure of GBPC. Recombinant GbpC111-552 (residues encompassing 111-552) was cloned into a pET23d vector, and thereafter expressed in E.coli BL21(DE3). GbpC111-552 purified initially using affinity chromatography (his-tag), followed by anion exchange (MonoQ) and finally polished with size exclusion (Superdex 75). GbpC111-552 was crystallized using the vapor diffusion method by scanning various commercial crystallization kits on a 96 well plate format through the Art Robbins Gryphon robot. Large crystals were obtained from a refined droplet condition that contained 1 μl of protein (43.3 mg/ml) mixed with 1 μl of reservoir made of 100 mM Bis-Tris pH 6.5 and 25% (w/v) PEG3350. The crystal structure could not be resolved by molecular replacement. Therefore crystals were soaked in Sodium Iodide (NaI) and thereafter flash frozen with 9% glycerol as crytoprotectant. MAD data sets were collected and the crystal structure was resolved. We will present the crystal structure, and how based on its structural homology we discovered similar functionalities among the surface proteins of S. mutans. The structural and functional studies of these surface proteins we hope would allow the identification of the adherence motifs, which would aid in development of inhibitors. The development of such anti-adhesive inhibitors would aid in disease preventative therapies.
Structure of a Novel Bacterial c-GMP Binding Protein
Authors: Chou Shan-Ho
Published: November 2015

cAMP is an important secondary messenger molecule widely distributed across all living kingdoms, whereas cGMP is generally considered to be restricted to eukaryotes. Recently, solid evidences for cGMP signaling in Rhodospirillum centenum have been provided, and it is proposed that cGMP could also be adapted to deliver messages to diverse outputs via unknown mechanisms. While the structures and functions of binding between cAMP and its receptor protein CRP have been well studied in the past, currently no structure of prokaryotic cGMP-binding protein complex is known. Here we report the first determination of a cGMP-receptor crystal structure from the plant pathogen Xanthomonas campestris (Xcc) to a resolution of 2.2 Å. The new cGMP receptor Xcc0249 is found to belong to the CRP/FNR family protein containing both a cyclic-Nucleotide Binding Domain (cNBD) and a GGDEF domains, and exhibits strong cGMP binding and diguanylate cyclase activities. Mutations of crucial amino acid residues responsible for cGMP binding to Xcc0249 are found to significantly reduce the biofilm formation and virulence in Xcc. Isothermal calorimetry (ITC) measurements demonstrate that Xcc0249 can bind preferentially to cGMP with a much stronger affinity (KD: 2.93E-7) than cAMP (KD: 1.79E-5). cGMP binding to Xcc0249 is also found to enhance the GGDEF diguanylate cyclase activity, implying a broader functional role of cGMP and a possible linkage between the cGMP and c-di-GMP interaction networks in bacteria. References
Structural and Functional study of Mevalonate Diphosphate Decarboxylase
Authors: Chen Chun-Liang , Stauffacher Cynthia
Published: November 2015

Mevalonate diphosphate decarboxylases (MDD) (EC 4.1.1.33) catalyze the Mg2+-dependent decarboxylation of mevalonate 5-diphosphate (MVAPP) by hydrolyzing adenosine triphosphate (ATP) and producing isopentenyl diphosphate (IPP) in the final step of mevalonate pathway. This enzyme is essential in Enterococcus faecalis and other Gram (+) bacteria; therefore, MDD protein is an ideal drug target for the treatment of bacterial infections. We have studied the enzyme kinetics and structures of MDD from Enterococcus faecalis (MDDEF) which causes clinical enterorococcal infections. In the crystal structure of the MDDEF bound with ATP, the catalytically unfavored orientation of the γ-phosphate of ATP implies that conformational changes of MDDEF might occur in order to accommodate the binding of ATP when the MVAPP binds to the active site in advance. A 10-fold decrease of the dissociation constrant (Kd) value of ATPγS has been observed using isothermal titration calorimetry (ITC) when MDDEF is pre-bound with MVAPP. The increase of binding affinity of ATPγS suggests that cooperative binding of ATP to MDDEF can be achieved by the prerequisite binding of MVAPP. Indeed, the crystal structure of MDDEF soaked with the MVAPP shows that one flexible loop that eventually should bind ATP becomes non-flexible and bends toward the active site of MDDEF. Thus, we hypothesize that the binding of the MVAPP to the active site triggers conformational changes of MDDEF which induces the binding of the other substrate, ATP, in its catalytically favored position. Further experiments will be performed for investigating a substrate-binding mechanism for MDDEF and these will serve as platforms for specific drug development in the near future.
Structural insights into DNA replication initiation in Helicobacter pylori
Authors: Bazin Alexandre , Cherrier Mickaël , Terradot Laurent
Published: November 2015

In Gram-negative bacteria, opening of DNA double strand during replication is performed by the replicative helicase DnaB. This protein allows for replication fork elongation by unwinding DNA and interacting with DnaG primase. DnaB is composed of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) connected by a flexible linker. The protein forms two-tiered hexamers composed of a NTD-ring and a CTD-ring. In Escherichia coli, the initiator protein DnaA binds to the origin of replication oriC and induces the opening of a AT-rich region. The replicative helicase DnaB is then loaded onto single stranded DNA by interacting with DnaA and with the AAA+ helicase loader DnaC. However, AAA+ loaders are absent in 80% of the bacterial genome, raising the question of how helicases are loaded in these bacteria [1]. In the genome of human pathogen Helicobacter pylori, no AAA+ loader has been identified. Moreover H. pylori DnaB (HpDnaB) has the ability to support replication of an otherwise unviable E. coli strain that bears a defective copy of DnaC by complementation [2]. In order to better understand the properties of HpDnaB we have first shown that HpDnaB forms double hexamers by negative stain electron microscopy [3]. Then, we have then solved the crystal structure of HpDnaB at a resolution of 6.7Å by X-ray crystallography with Rfree/Rfactor of 0.29/0.25. The structure reveals that the protein adopts a new dodecameric arrangement generated by crystallographic three fold symmetry. When compared to hexameric DnaBs, the hexamer of HpDnaB displays an original combination of NTD-ring and CTD-ring symmetries, intermediate between apo and ADP-bound structure. Biochemistry studies of HpDnaB interaction with HpDnaG-CTD and ssDNA provides mechanistic insights into the initial steps of DNA replication in H. pylori. Our results offer an alternative solution of helicase loading and DNA replication initiation in H. pylori and possibly other bacteria that do not employ helicase loaders.
Crystal structure of the Csd3 protein from Helicobacter pylori
Authors: An Doo Ri , Suh Se Won
Published: November 2015

The helical cell shape of Helicobacter pylori facilitates the penetration of thick gastric mucus and promotes virulence. The peptidoglycan plays a structural role in the bacterial cell wall and its controlled modification is essential for determining the helical shape. Several H. pylori genes were identified to contribute to its helical cell shape through alterations in peptidoglycan crosslinking and trimming of the peptide (Sycuro et al., 2010; Sycuro et al., 2012). One of them is the hp0506 gene that encodes a putative periplasmic peptidase belonging to the M23-family of zinc-metallopeptidase (Sycuro et al., 2010). The HP0506 protein carries out not only a D,D-endopeptidase activity but also a D,D-carboxypeptidase activity. Hence, it has been named Helicobacter D,D-peptidase A (HdpA) and cell shape determinant 3 (Csd3). Csd3 is the first enzyme belonging to the M23-peptidase family that can perform the D,D-carboxypeptidation to regulate the cell shape (Mathilde et al., 2010). To gain structural and functional insights at the molecular level, we have determined the crystal structure of Csd3 at 2.1 Å resolution by using the Pt SAD data. H. pylori Csd3 consists of three domains including a LytM domain, which contains the highly conserved active site motif among the M23 metallopeptidase family. An anomalous scattering experiment with Zn2+ confirmed the metal-binding site in the active site. The Zn2+ ion is tetrahedrally coordinated and a catalytic water for peptide hydrolysis is absent in the active site of Csd3. Furthermore, domain 1 blocks the active site, thus prohibiting the substrate peptide binding. Our mass analysis shows that the full-length Csd3 is inactive as the D,D-carboxypeptidase. These results suggest that proteolytic processing may be necessary for the activation of Csd3.
Predicting crystallisation propensity of small molecules
Authors: Wicker Jerome , Cooper Richard , David William
Published: November 2015

We show that suitably chosen machine learning algorithms can be used to predict the "crystallisation propensity" of classes of molecules with a promisingly low error rate, using the Cambridge Structural Database and ZINC database to provide training examples of crystalline and non-crystalline molecules. Supervised learning tasks involve using machine learning algorithms to infer a function from known training data which allows classification of unknown test data. Such algorithms have been successfully used to predict continuous properties of compounds, such as melting point[1] and solubility[2]. Similar methods have also been applied to protein crystallinity predictions based on amino acid sequences[3], but little has previously been done to attempt to classify small organic molecules as crystalline or non-crystalline due to the difficulty in finding descriptors appropriate to the problem. Our approach uses only information about the atomic types and connectivity, leaving aside the confounding effects of solvents and crystallisation conditions. The result is reinforced by a blind microcrystallisation screening of a sample of materials, which confirmed the classification accuracy of the predictive model. An analysis of the most significant descriptors used in the classification is also presented, and we show that significant predictive accuracy can be obtained using relatively few descriptors.
Structural and electronic behaviour of MoS2, MoSe2and MoTe2at high pressure
Authors: Grajcarova Liliana , Riflikova Michaela , Martonak Roman , Tosatti Erio
Published: November 2015

Using ab initio calculations and metadynamics simulations we studied the behaviour of layered semiconducting transition metal dichalcogenides, MoX2 (X = S, Se, Te) at high pressure with focus on structural transitions and metallization [1,2]. We found that concerning structure, the behaviour of MoS2 is different from that of MoSe2 and MoTe2. In MoS2 pressure induces at 20 GPa a structural transition where layer sliding takes place, bringing the initial 2Hc stacking to a 2Ha stacking typical of e.g. 2H-NbSe2. This finding naturally explains previous X-ray diffraction and Raman spectroscopy data and was very recently confirmed by new X-ray diffraction experiments[3]. On the other hand, this transition does not occur in MoSe2 and MoTe2 where instead the initial 2Hc stacking remains stable. Besides structural changes pressure in MoS2 induces also a semiconductor - semimetal transition which takes place by band overlap and closing of indirect band gap. This electronic transition occurs in the same region where the structural transition takes place, at 25 GPa in the 2Hc phase and at 20 GPa in the 2Ha phase. In case of MoSe2 and MoTe2 a very similar electronic transition leading to semimetal is predicted to occur at 28 GPa and 13 GPa, respectively. All three materials exhibit after metallization a low density of states at the Fermi level implying low superconducting temperature (if any). Due to absence of structural transition in the metallization region MoSe2 and MoTe2 could be suitable candidate materials for observation of the excitonic insulator phase.
First-year experience with fully automated crystal structure prediction
Authors: Neumann Marcus , Doser Bernd
Published: November 2015

With improving hardware and software performance, usability has become one of the main obstacles to a more widespread use of Crystal Structure Prediction (CSP) with the GRACE program. In terms of method development, important milestones had already been passed by the time of the 5th blind test [1] in 2010, including the parameterization of dispersion-corrected Density Functional Theory (DFT-D) [2], the generation of tailor-made force fields from ab-initio reference data [3], a Monte-Carlo parallel tempering crystal structure generation engine and a DFT-d reranking procedure exploiting statistical correlations. These components have now been incorporated in automated data flow processes that remove the burden of scores of expert decisions from the user. Summarizing the results of CSP studies performed with the new Force Field Factory and CSP Factory modules throughout a year, the current performance of CSP is critically assessed and further method development needs are pinpointed. Studied compounds include 20 small molecules with competing hydrogen bonds motifs, 4 mono-hydrates of non-ionic molecules and the hydrates and chloride salts of several amino acids. The ability to handle flexible pharmaceutical molecules is demonstrated by a validation study on aripiprazole with one and two molecules per asymmetric unit. Salient features of the energy landscapes of other pharmaceutical molecules are discussed. Statistics are presented for the accuracy of tailor-made force fields, and the energy ranking performance of several DFT-d flavors is compared.
Strain And Symmetry-induced Structural Transitions in Ultra-thin BiFeO3 Films
Authors: Schlepuetz Christian , Yang Yongsoo , Senabulya Nancy , Adamo Carolina , Beekman Christianne , Siemons Wolter , Christen Hans , Schlom Darrell , Clarke Roy
Published: November 2015

As one of very few room temperature multiferroic materials, bismuth ferrite (BiFeO3: BFO) has been studied extensively in recent years. The bulk form of BFO is known to have a rhombohedrally distorted quasi-cubic perovskite structure with an (a–,a–,a–) octahedral tilt pattern, exhibiting both anti-ferrodistortive displacements and a spontaneous polarization along the <111> axes. Investigating epitaxial thin films under compressive strain, several studies have reported that the polarization direction is tilted towards the [001] out-of-plane direction, while maintaining a significant in-plane component. This effect is accompanied by a significant enhancement of the spontaneous polarization and a series of phase transitions from rhombohedral (R) for small strains to R-like monoclinic (MA) to T-like monoclinic (MC) and to tetragonal (T) for larger strains [1]. Through synchrotron-based 3-dimensional reciprocal space mapping (RSM), facilitated by using X-ray area detectors (Pilatus 100K pixel detector), we have investigated the structure of ultra-thin BFO films grown on SrTiO3 (STO), LaAlO3 (LAO), and TbScO3 (TSO) substrates with thicknesses of only several unit cells. In this thickness regime, the influence of the substrate atomic structure on the properties of the ultra-thin films is very pronounced, and the films exhibit perfect heteroepitaxy up to a critical thickness when the build up of strain energy forces the films into a relaxed structure. Both on STO [2] and LAO, the ultra-thin BFO undergoes a monoclinic to tetragonal phase transition, but with very different c/a axis ratios. On TSO, a very pronounced and well-ordered stripe domainstructure evolves where the domain sizes are strongly thickness- dependent. Argonne National Laboratory's work was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract DE-AC02-06CH11357.
Direct visualization of subcritical nuclei in molecular film growth
Authors: Schwarz Daniel
Published: November 2015

The growth and structure of 4,4'-biphenyldicarboxylic-acid (BDA) on Cu(001) at temperatures between 300 K and 400 K was studied by LEEM and μ-LEED. BDA is a linear molecule consisting of two phenyl rings with a carboxylic-acid group at opposite ends. During growth on Cu(001) the adsorbed BDA molecules form first a disordered 2D gas phase. Once this phase reaches a sufficiently large density, a crystalline phase nucleates, in which the molecules form a hydrogen-bonded 2D supramolecular network. By a careful analysis of the LEEM bright-field image intensity we can measure the density of the 2D gas phase, which is up to 40% of that in the crystalline phase. From the equilibrium densities at different temperatures we can construct the 2D phase diagram and extract the cohesive energy (0.35 eV). During the distinct nucleation period we can observe a fascinating phenomenon: sub-critical nuclei form, grow up to 4000 nm2in size and decay with lifetimes of several seconds. These sizes are considerably larger than what is usually seen in epitaxial growth and we explain this observation with the relatively weak intermolecular interactions.
Structural basis for VPg-induced formation of RNA-dependent RNA polymerase multimeric complexes
Authors: Lee Ji-Hye , Chung Yeon Bin , Seok Jong Hyeon , Han Kang Rok , Kim Sella , Kim Kyung Hyun
Published: November 2015

Norovirus is the leading cause of epidemic acute, nonbacterial gastroenteritis, and adopts de novo and VPg (Virion protein genome linked)-primed RNA synthesis by RNA-dependent RNA polymerase (RdRp). To understand the interaction between RdRp and VPg in replication of murine norovirus-1 (MNV-1), we determined the crystal structure of MNV-1 RdRp-VPg(1-73)-RNA complex. VPg was bound to the base of the palm domain and the tip of the fingers domain of RdRp simultaneously, but RNA template could not be modeled. The binding affinity constants (Kd) for RdRp-VPg was 3.7411.57 nM and VPg(1-73) showed approximately 90-fold less affinity than that of full-length VPg. In addition to this multiple binding mode, VPg enhanced the interactions of RdRp hexamers, leading to the formation of high-order multimers or tubular fibrils with significantly increased polymerase activity, confirmed by electron microscopic and biochemical studies. Our data indicated that MNV-1 VPg with helical structure was bound to RdRp at multiple sites and induces RdRp multimerization in viral replication. The multimers of RdRp-VPg-RNA can provide a mechanistic understanding of viral polymerase multimeric arrays and a new tool for development of antivirals to control norovirus outbreaks. This work was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare and Family Affairs (A085119 K.H.K), Basic Science Research Program through the National Research Foundation (NRF-2013R1A1A2064940, L.J-H), Korea University Grant (L.J-H), and the BK21 plus program of the Ministry of Education, Korea.
Enthalpic cost of water removal from a glucose binding cavity on HK620 TSP
Authors: Gohlke Ulrich , Broeker Nina , Heinemann Udo , Seckler Robert , Barbirz Stefanie
Published: November 2015

Bacteriophage HK620 recognizes and cleaves the O-antigen polysaccharide of Escherichia coli serogroup O18A1 with its tailspike protein (TSP). HK620TSP binds hexasaccharide fragments with low affinity, but single and double amino acid exchanges generated a set of high-affinity mutants with submicromolar dissociation constants. Isothermal titration calorimetry showed that only small amounts of heat were released upon complex formation via a large number of direct and solvent-mediated hydrogen bonds between carbohydrate and protein. At room temperature, association was both enthalpy- and entropy-driven, emphasizing major solvent rearrangements upon complex formation. Crystal structure analysis of a complete set of combinations of wildtype protein and point mutations with and without polysaccharide ligands was carried out. It could be shown that the extended sugar binding site can be dissected into two regions: first, a hydrophobic pocket at the reducing end with minor affinity contributions. Second, a region where the specific exchange of amino acids creates a site for additional water molecules. Sidechain rearrangements upon sugar binding lead to desolvation and additional hydrogen bonding which define this region of the binding site as the high-affinity scaffold.
Impact of crystal packing on coiled-coil flexibility.
Authors: Ferron François , Blocquel David , Habchi Johnny , Durand Eric , Sevajol Marion , Erales Jenny , Papageorgiou Nicolas , Longhi Sonia
Published: November 2015

The structural characterization of various constructs of the Measles virus (MeV) Phosphoprotein (P) multimerization domain (PMD) has brought to light significant discrepancies in the quaternary structure due to both crystal constraints and the flexible nature of this coiled-coil. Indeed, despite a conserved tetrameric parallel coiled-coil core, structural comparison unveiled significant deformations in the C-terminal extremities that even led to the partial unfolding of the coiled-coil. These deformations were induced by intermolecular interactions within the crystal, as well as by the crystallization condition. These deformations also suggest that PMD has the ability to adapt to external mechanical constrains. Using a combination of biophysical methods (size-exclusion chromatography, circular dichroism and small angle X-ray scattering), we assessed the differential flexibility of the C-terminal region of the MeV PMD in solution. Taken together, these results show that crystal packing can be used to "freeze" in a certain state, parts of proteins known to be in a dynamic folding-unfolding equilibrium. They also bring awareness that conclusions about function and mechanism based on analysis of a single crystal structure of a known dynamic protein can be easily biased, and they challenge to some extent the assumption that coiled-coil structures can be reliably predicted from the amino acid sequence.
ASAXS measurements with soft (tender) X-rays to control the contrast
Authors: Okuda Hiroshi , Yamamoto Takayoshi , Takeshita Kohki , Hirai Mitsuhiro , Sakurai Shin-ichi , Kitajima Yoshinori , Igarashi Noriyuki , Shimizu Nobutaka , Ogawa Hiroki
Published: November 2015

The structure and properties of thin soft matter materials might be better examined in detail by scattering measurements when the contrast between the materials and penetration depth are tunable. In the so-called tender X-ray region, there are several elements of interest for small-angle scattering measurements, such as Mg, Al, Si, P, and S. We worked on GISAXS measurements at K absorption edges of Si and P to control contrast and penetration depth for thin block copolymer (SEBS) samples and phospholipid alloy systems comprising of phospholipid (PC, DPPC), cholesterol, and ganglioside, and SAXS at Al for Al alloys. The photon energy used in the present measurements is soft enough to give large anomalous effect in the real part of refractive indices for light elements, yet hard enough so that the scattering vector required for nanostructure analysis can be covered. By choosing the photon energy at the K absorption edge of Si, the contrast between Si substrate and polymer thin film can be suppressed, thereby suppressing dynamical effect in GISAXS intensity caused by reflected beam[1]. Combined with the depth sensitive analysis, this is useful to examine the nanostructures that are changing with the distance from the surface. Concerning the contrast change inside the thin films, change of the GISAXS intensities from PC (phosphatidylcholine)-cholestrol-ganglioside (GD1) films spin-cast on Si substrates have been examined at the K absortpion edge of P [2]. ASAXS for P has been examined by Stuhrmann and coworkers[3], but the number of works after them is not large. Present measurements using image plates showed that the hexagonal phase appearing in dried phospholipid alloy films suggests a contrast reversal with the photon energy.
ASAXS quantifies counterion distributions around DNA and RNA
Authors: Pollack Lois
Published: November 2015

Because both RNA and DNA carry large negative charge, interaction with oppositely charged partners is required for folding to functional structures. For example, counterions fold RNA and condense DNA. Despite these important roles, ion detection remains elusive. I describe the application of anomalous SAXS methods that highlight the contribution to the scattering signal arising from counterions [1]. In addition to measuring ion distribution, we also count the number of excess ions surrounding a nucleic acid structure [2,3]. Taken together, measurements of ion number and spatial distribution provide an understanding of the relationship between counterions and nucleic acid structure. Present ASAXS work in the Pollack lab is supported by the NIH through grants R01 GM085062 and R01 GM099450.
Polymorphic stability of progesterone under stress conditions
Authors: Araya-Sibaja Andrea , Fandaruff Cinira , Campos Carlos Eduardo , Silva Marcos Antônio , Cardoso Simone , Vega-Baudrit José Roberto , Cuffini Silvia
Published: November 2015

Progesterone (PRG) is an essential hormone in regulating the female reproductive system. It is used in gynecology, including contraception, medical abortion, and treatment of conditions related to endometrial and myometrial growth [1]. This drug exhibits two different crystal structures: forms 1 (PRG-1) and 2 (PRG-2); both with equal pharmacological effects. PRG-2 is the metastable form and it is 1.1 kcal/mol less stable than PRG-2 [2]. Polymorphic instability occurs when a metastable solid form (PRG-2) transforms into the most thermodynamically stable (PRG-1) [3]. It is well-known the therapeutic efficacy of a drug substance or drug product can be altered by its polymorphic or chemical transformation [4]. In order to study the polymorphic stability both polymorphs, PRG-1 and PRG-2, were placed under the same mechanical, thermal and high humidity stress conditions. X-ray powder diffraction (XRPD) analysis showed PRG-2 maintained its crystal structure after 3 months of exposure to dark storage condition at 400C/75% relative humidity and 1 month to light. High performance liquid chromatography (HPLC) showed no degradation of PRG-1 and PRG-2. However, mechanical stress (grinding) on PRG-2 produced seeds of PRG-1 that induced its polymorphic transformation (Figure 1A). DSC curve showed and endothermic events at 120.70C corresponding to the melting point of PRG-2 followed by the recrystallization at 123.80C of PRG as PRG-1, finally the fusion of PRG-1 at 127.90C. The Ea average value was higher in PRG-2 than in PRG-1; it suggested PRG-2 is more thermally stable than PRG-1 and, the decomposition behavior is different between these two polymorphs. Degradation products from thermal stability studies were monitored by coupled TGA-FT-IR analyses and different analyses (Table 2 inset in Figure 1). PRG-1 shows a high maximal rate of degradation (Tdmax) and initial temperature of thermal decomposition (To) compares to PRG-2.
Occurrence of polymorphism in famotidine raw materials
Authors: Ângelo Marilene , Jacon Jennifer , Santos Olimpia Maria , Cazedey Edith Cristina , Bonfilio Rudy , Doriguetto Antônio Carlos , Benjamim de Araújo Magali
Published: November 2015

Polymorphs are compounds with the same chemical composition, however the molecules are arranged in at least two different ways in the solid state. Famotidine is a histamine H2-receptor antagonist inhibitor of gastric secretion and widely used in gastric and duodenal ulcer disease. Two polymorphs are described for famotidine, A and B. The polymorph A is the most thermodynamically stable form and polymorph B is the kinetically favored form being marketed because it presents greater pharmacological activity. The aim of this study was to evaluate the occurrence of famotidine polymorphs in five raw materials acquired from different suppliers. The reference standard (USP) was also analyzed. All samples were characterized by powder X-ray diffraction (PXRD), infrared spectrophotometry (IR-ATR) and differential scanning calorimetry (DSC). PXRD analysis enables us to identify form B in five raw material samples and in the reference standard (USP). However, one of the raw materials additionally shows the presence of polymorphic form A. The DSC and IR-ATR techniques were essential to identify the polymorphic forms of famotidine confirming the results obtained by PXRD. Since the presence of polymorphs can compromise the effectiveness and safety of medicines and there is no official methodology of analysis and control of polymorphism in famotidine raw materials, the polymorphic contamination found in this study are being further analyzed and their physicochemical properties are being evaluated.
Synthesis and crystal structure of a new anticancer candidate: RPF151
Authors: Tavares Maurício , Damião Mariana , Ferreira Adilson , Rodrigues Cecilia , Barbuto José , Azevedo Ricardo , de-Sá-Junior Paulo , Parise-Filho Roberto , Ferreira Fabio
Published: November 2015

This work reports on the synthesis, crystal structural determination, conformational analysis and antiproliferative activity of an alkylsulfonamide analogue of capsaicin – RPF151 (N-(benzo[d][1,3]dioxol-5-ylmethyl)butane-1-sulfonamide). Capsaicin is the primary pungent and irritating natural product present in a variety of red chilli peppers of the genus Capsicum, and was reported to selectively inhibit the growth and to induce apoptosis in a wide variety of tumour cell lines.1-3 RPF151 was obtained by a simple reaction of 1-butanesulfonyl chloride with piperonylamine, in an anhydrous DCM (dichloromethane) and TEA (tetraethylammonium) mixture (Yield 70%). The crystal structure determination was carried out by means of an ab initio simulated annealing approach using X-ray powder diffraction data. RPF151 crystallized under a monoclinic system (P21/a) with final unit cell parameters refined using the Rietveld method: a = 29.0171(13) Å, b = 10.4745(3) Å, c = 9.1117(3) Å, β = 104.268(4)0, V = 2683.98(17) Å3, Z = 8, Z' = 2. The statistical parameter as well as R-factors were: χ2 = 1.11, Rwp = 0046, Rexp = 0.042 and RBragg = 0.010. The molecules are held together along the c-axis by hydrogen bonds involving the atoms N(37)–H(42)···O(4). Calculated elemental analysis for C12H17NO4S (271.09 g mol-1) shows C = 53.12, H = 6.32 and N = 5.16 while experimental values are C = 53.13, H = 6.39 and N = 5.14. The effects of RPF151 10 μM on human umbilical vein endothelial cells (HUVEC) proliferation was tested by flow cytometry. It was verified that RPF151 induced changes on cell morphology, a fact corroborated by HUVEC cell size and complexity. Furthermore, it caused a significant reduction on cell proliferation and evidenced no cytotoxic effects. Therefore, RPF151 could be developed as a candidate to an anti-angiogenic drug for the fighting against cancer. Acknowledgments: We are grateful to FAPESP (proc. nr.: 2013/18160-4, 2012/23233-8 and 2008/10537-3), CNPq (proc. nr. 305186/2012-4 and 477296/2011-4) and Provost's Office for Research of the University of São Paulo for financial support.
Electron Momentum Density: Recent Progress and Perspective for Combined Studies
Authors: Sakurai Yoshiharu
Published: November 2015

Quantum mechanical descriptions are becoming a focus of attention in understanding the behavior of wide classes of materials. This paper discusses some of our recent works related to charge or magnetic Compton scattering studies. Selected topics include: (1) Quantum modelling of doped holes in high-Tc cuprates [1], which provides insight into the dome-shaped doping dependence of the superconducting transition temperature. (2) Analyses of Compton scattering X-ray spectra in spin-crossover cobaltates, which allows us to delineate the t2g-eg physics and quantum chemistry from the temperature evolution of electron momentum density. As a conclusion remark, we show an example of combined studies [2] and present its perspective, emphasizing that X-ray Compton scattering is highly sensitive to delocalized or itinerant electrons.