bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure of viral spindles, in vivo crystals boosting insecticidal activity
Authors: Hijnen Marcel , Boudes Marion , Aizel Kaheina , Olieric Vincent , Schulze-Briese Clemens , Bergoin Max , Coulibaly Fasseli
Published: November 2015

Entomopoxviruses (EV) produce two types of microcrystals in infected cells: virus-containing spheroids representing their main infectious form; and spindles, bipyramidal crystals of the viral fusolin protein, that contribute to the oral virulence of these viruses. In co-feeding experiments, spindles also enhance the insecticidal activity of unrelated insect pathogens, which suggested their use as bioinsecticide additives. To understand how fusolin contributes to virulence and assembles in vivo, we determined the structures of EV spindles by X-ray microcrystallography using crystals isolated from EV-infected common cockchafers. This structure reveals that fusolin is composed of a fibronectin III domain followed by an extended C-terminal molecular arm (CT). The globular domain is structurally homologous to CBP21, a protein that is secreted by Gram-negative bacteria to degrade chitin as a source of energy. Like CBP21, fusolin has all the hallmarks of a lytic polysaccharide monooxygenase enzyme (LPMOs) with two conserved histidine residues forming a copper binding site and a prominent di-tryptophan motif positioned to bind the planar surface of crystalline chitin. The LPMO domain assembles in vivo into ultra-stable crystals crosslinked by CT. This molecular arm mediates the formation of domain-swapped dimers and their assembly into a crystalline lattice stabilized by a 3-D network of inter-dimer disulfide bonds. Overall, the molecular organization of spindles indicates a mode of action where controlled released of the LPMO domain of fusolin by proteolytic removal of the CT extension leads to disruption of the chitin-rich peritrophic matrix of larvae to facilitate the initial steps of viral invasion of the host.
Complex structure of MERS-CoV spike glycoprotein with human receptor DPP4
Authors: Wang Nianshuang , Jiang Liwei , Shi Xuanling , Poon Kwok-Man Vincent , Yuen Kwok-Yung , Zheng Bo-Jian , Zhang Linqi , Wang Xinquan
Published: November 2015

Recently identified the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in human. No prophylactic and therapeutic agents specifically against MERS-CoV are currently available. Entry of MERS-CoV into the target cells depends on binding of receptor-binding domain (RBD) on viral envelope spike glycoprotein to the cellular receptor dipeptidyl peptidase 4 (DPP4). We report the 3.0 angstrom-resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of DPP4. The structure shows that MERS-CoV RBD consists of a core and a receptor binding subdomain. MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor binding subdomain. Structural and mutagenesis analyses identified several key residues in the receptor binding subdomain of RBD that are critical for viral binding to DPP4 and entry into the target cell. Two RBD-specific potent human neutralizing monoclonal antibodies were derived from single-chain variable region fragments (scFvs) of nonimmune human antibody library. They inhibited infection of both pseudotyped and live MERS-CoV with IC50 at nanomolar concentration. Biochemical analysis indicated that these two antibodies blocked RBD interaction with DPP4 on the cell surface.
The Icosahedral øX174 Phage Forms a Tail Structure Essential for Infectivity
Authors: Sun Lei , Young Lindsay , Boudko Sergei , Fokine Andrei , Rossmann Michael , Fane Bentley
Published: November 2015

PhiX174 is a small circular ssDNA icosahedral phage of known structure (McKenna et al., 1992). The infectious viral capsid consists of 60 copies of the major capsid protein F, 60 copies of the spike protein G, 60 copies of the DNA binding protein J as well as about 12 copies of the DNA pilot protein H. We have shown that the H protein can assemble in vitro and in vivo into tubes that are wide enough to allow the passage of two antiparallel strands of ssDNA. We will give details of our mutational and cryo electron tomographic analyses showing that these tubes are required for the translocation of the viral genome into the cytoplasm of the E.Coli host. Thus the mechanism of infection of tail-less phages like phiX174 and of tailed phages may be a case of convergent evolution.
Structural studies of Rhino protein in piRNA biogenesis
Authors: Huang Ying , Yu Bowen
Published: November 2015

Small-RNA-guided gene regulation is a common biological process in eukaryotic cells. Animal germ cells are characterized by an intriguing small-RNA-mediated gene-silencing mechanism known as PIWI pathway. PIWI-interacting RNAs (piRNAs) are small, 21-30 nt single-stranded RNAs that associate with PIWI proteins. The function of piRNA is silencing transposon elements in germ line cells to keep the genome integrity since germ line cells are the only source for transmitting genetic information to the next generation. For a long time the biogenesis of piRNA and the mechanism of how it functions remains unclear. The biogenesis of piRNAs is quite different from that of other small-RNA pathways, which is independent of Dicer. piRNA biogenesis occurs through both primary and secondary pathway (or called ping-pong cycle). In drosophila transcripts from heterochromatic clusters are processed into primary piRNAs. A particularly fast evolving homologue of heterochromatin protein 1 (HP1) called Rhino binds to dual-strand piRNA clusters and is required for their production. But how does Rhino recognize histone H3 trimethylated on lysine 9? What's the difference between Rhino and other HP1 proteins? Here we show the crystal structure of Rhino both in apo form and complex form with H3K9me3. We observed a unique dimer interface in Rhino and a domain-swapping in conformational change. These findings provide insights into the molecular mechanism of the specificity of Rhino recognizing histone H3K9me3 and its function in piRNA biogenesis.
A Macromolecular approach to peptide-based molecular recognition and catalysis
Authors: Baxter Richard
Published: November 2015

Synthetic peptides incorporating non-natural amino acids provide an opportunity to apply biomimetic principles in the design of both chemical scaffolds and novel pharmaceuticals. Crystallographic analysis can be of significant utility in this area just as elsewhere, but blur the line between small-molecule and macromolecular systems. I will present recent examples combining the tools of macromolecular crystallography techniques with chemical biology to elucidate structures of peptide-based binding and catalytic motifs. First, I will discuss recent structures of a beta-peptide known to spontaneously self-assemble into a octameric bundle wih a defined tertiary-fold. By introducing a non-natural amino acid at the solvent-exposed surface, a binding epitope for poly-alcohols is introduced. [1] Conversely, by modifying the hydrophobic core, the tertiary fold can be re-organized. [2] Second, I will discuss a peptide-based catalyst for the site-specific modification of saccharide units in the scaffold of the antibiotic teicoplanin. [3] While glycosylated small-molecules can be challenging structural-targets, native chemical ligation of the peptide to a macromolecular scaffold allowed for structure determination of the peptide and its binding target. Further structure-based design of more complex non-natural amino acid structures is a promising route to novel peptide-based tools and therapeutics.
Chromatin recognition and regulation of the acetyltransferase CBP/p300
Authors: Panne Daniel
Published: November 2015

Gene regulation in higher eukaryotes requires recruitment of the transcriptional co-activators CBP/p300 that associate with transcriptional regulators and integrate a large number of signal transduction pathways. Recruitment of CBP/p300 results in acetylation and remodeling of inhibitory chromatin. Recently we have determined the 2.8Å crystal structure of the catalytic core of p300 containing its Bromodomain, the CH2 region and HAT domain in complex with the bi-substrate inhibitor, Lys-CoA. Unexpectedly the structure reveals that the CH2 region contains a discontinuous PHD domain which is interrupted by a RING domain. The Bromodomain, PHD, RING and HAT domains adopt an assembled configuration in which the RING domain is positioned over the HAT substrate binding pocket. Disease mutations that disrupt RING attachment lead to upregulation of HAT activity, revealing an auto-inhibitory role for this domain. Detailed investigation of chromatin substrate recognition showed that the Bromodomain preferentially interacts with histones containing combinations of acetylations rather than singly modified sequences, whereas the p300 PHD domain did not interact with canonical substrates. Our results demonstrate that the Bromodomain substrate specificity is compatible with HAT substrate acetylation patterns suggesting that positive feedback is likely an important component in establishment of active chromatin states. We here present progress in our understanding of the regulation of p300 activity, chromatin modification, readout and how disease-related mutations result in dysregulation of these activities.
Structure and substrate selectivity of PvuRts1I
Authors: Zang Jianye , Shao Chen , Wang Chengliang
Published: November 2015

5-hydroxymethylation is a mysterious modification of cytosine discovered decades before, with its functional roles awaiting elucidation in eukaryotes. Cumulative evidence demonstrates that 5-hydroxymethylcytosine is an epigenetic marker serves critical roles in multiple biological processes. Moreover, the profile of 5-hydroxymethylcytosine is changed under disease conditions such as cancer. Several methods including AbaSI-coupled sequencing have been developed to decipher hydroxymethylome at single-base resolution. However, the technical hurdles of AbaSI-coupled sequencing derived from the enzymatic property of AbaSI, a member belonging to PvuRts1I family endonuclease, may impede the application of this method. PvuRts1I is a modification dependent endonuclease with high selectivity to 5-hydroxymethylcytosine over 5-methylcytosine and cytosine. To improve the substrate selectivity of PvuRts1I family member, we solved the crystal structure of PvuRts1I. One nuclease domain and one SRA-like domain are located at the N- and C-terminal half of the structure, respectively. In comparison with other SRA domain structures, the SRA-like domain of PvuRts1I has been proposed to be the 5-hmC recognition module. Several mutants of PvuRts1I with enzymatic activity to 5-hydroxymethylcytosine only have been generated based on structural analysis, providing perfect candidates for dissection of hydroxymethylome from methylome.
Molecular basis of the selective methylation of histone H3.1
Authors: Couture Jean-Francois
Published: November 2015

Histone proteins are critical components of the chromatin fiber. With the exception of histone H4, histone proteins exist as different variants with assigned specialized functions and are proposed to act as key elements for the selective deposition of histone post-translational modifications (PTMs). Among these variants, H3.3, which differs from H3.1 by only 5 residues, has been predominantly found in the proximity of genes that are highly expressed; however the functional consequences of that marking have remained enigmatic. Herein we report the crystal structure of the trithorax-related SET domain histone H3.1 K27 methyltransferase ATXR5 in complex with histone H3.1 and the product cofactor S-adenosylhomocysteine. Overall, the SET domain folds as an all β-strands structure preceded by the pre-SET domain which folds as three long α-helices. The histone H3 is maintained in an elongated conformation by residues located both in the SET and pre-SET domains of ATXR5. Interestingly, we found that a three residue loop folds back on top of the ATXR histone H3.1 binding cleft shielding the peptide from the solvent and maintaining P30 and A31 of H3.1 in a shallow hydrophobic pocket. Strikingly, substitution of A31 for a threonine, the corresponding residue in histone H3.3 in plant, severely impairs ATXR5 methyltransferase activity. Finally, biochemical and structural studies revealed that, with the exception of R26 mono-methylation, post-transcriptional modifications of residues neighboring K27 is detrimental to ATXR5 activity. Overall, our results suggest that the deposition of H3.3 serves to prevent K27 mono-methylation and heterochromatin formation during DNA replication.
Correlated scattering: probing atomic structure of molecules and nanoparticles
Authors: Mendez Derek , Lane Thomas , Sung Jongmin , Ratner Daniel , Watkins Herschel , Doniach Sebastian
Published: November 2015

In 1977, Z. Kam theorized that correlations of scattering patterns, measured by exposing a solution of randomly oriented identical particles to x-ray radiation, could yield detailed information on the internal structure of the individual particles [1]. During a single exposure (whose duration should be short compared to the particle rotational diffusion time), physical correlations arise whenever multiple photons scatter from the same particle into different directions. By averaging correlations from many exposures, we have demonstrated that one can extract this correlated signal from a background of uncorrelated single-direction scattering events from different particles [2]. This additional information can be used to place constraints on model structures of the particles under investigation, providing a method of structure refinement to atomic resolution. We recently observed correlated scattering from solutions of ~10^9 silver nanoparticles exposed to synchrotron radiation at a microfocus beamline at SSRL [2]. By auto- and cross- correlating the Bragg rings 111 and 200, five correlation peaks were resolved corresponding to the structure and symmetry of silver's reciprocal lattice. To transition from nanoparticles to biomolecule studies, we have performed several experiments at x-ray free electron laser centers (SLAC and SPring-8), and are working to refine analysis techniques.
ASAXS Study on Spatial Distribution of Hydrophobic Compounds in Polymer Micelles
Authors: Akiba Isamu , Nakanishi Ryosuke , Kugimoto Masaki , Kugimoto Daisuke , Sanada Yusuke , Sakurai Kazuo
Published: November 2015

In drug delivery system (DDS) using polymer micelles as drug carrier, DDS properties are related to spatial distribution of drug compounds in the micelles [1]. Because the spatial distribution of drug compounds should strongly depend on interactions and solubility of drug compounds in the micelles, elucidation of the relation between chemical structures of drug compounds and their spatial distribution in the micelle is much important. Thus, in this study, we examine to elucidate the relation between chemical features and spatial distribution of drug compounds in polymer micelles by using anomalous small-angle X-ray scattering (ASAXS). To apply the ASAXS near bromine K-edge for analysis [2] of spatial distribution of drug compounds in polymer micelles, we employ 4 different bromine-labeled hydrophobic compounds as model drug compounds and polymer micelles composed of poly(dimethylaminoethyl methacrylate)-block-poly(methyl methacrylate) (PDMAEMA-b-PMMA). Figure shows SAXS and resonant term obtained from ASAXS near bromine K-edge for the polymer micelles containing 9-bromofluorene (BrF). The domain size estimated from the resonant term is much smaller than that of hydrophobic PMMA core of the micelle. Therefore, When BrF, which is highly hydrophobic and scarcely dissolved in hydrophobic PMMA, is incorporated in the polymer micelle, BrF forms small droplet in the hydrophobic core composed of PMMA. For the micelles incorporating bromobenzene, which as similar properties of BrF, similar result is obtained. On the other hand, 4-bromobenzyl alcohol and ethyl 2-bromoethyl propionate, which are miscible with PMMA, are homogeneously dispersed in the PMMA core of the micelles. These results indicate that highly hydrophobic compounds forms small droplet in hydrophobic core, and introduction of polarity to the compounds causes expansion of the area existing the hydrophobic compounds in polymer micelle.
Neutron powder diffraction analysis of guanosine dihydrate using MEM
Authors: Sugawara Yoko , Yamamura Shigefumi , Hoshikawa Akinori , Ishigaki Toru , Kamiyama Takashi
Published: November 2015

In majority of the crystals of pharmaceutical compounds, hydrogen bonds play a crucial role. Determination of a hydrogen position is highly important, in order to investigate hydrogen bonds especially in the case of hydrates. We have been investigating humidity-induced phase transitions of hydrates systematically [1,2]. Unique characteristics of hydration water molecules have prompted us to explore the phenomena more precisely. Neutron diffraction analysis is a powerful tool to determine hydrogen positions. However, large single crystals are required because of weak neutron diffraction intensities. Under such background, we carried out neutron powder diffraction analysis of guanosine dihydrate using the Maximum Entropy Method (MEM). Neutron powder diffraction data of guanosine dihydrate (C10H13N5O5.2H2O; crystal data: monoclinic, space group P21, a = 17.518, b = 11.278, c = 6.658 Å, β= 98.170, Z = 4) were measured by iMATERIA at MLF in J-PARC (Figure 1(a)). Rietveld analysis was carried out using atomic coordinates of non-hydrogen atoms determined by X-ray analysis and those of hydrogen atoms which were placed on the geometrically calculated positions using the averaged X-H bond lengths determined by neutron analysis referencing the hydrogen positions estimated by X-ray analysis. Using Fo and σ by Rietveld analysis, the nuclear density distribution was calculated by MEM (Figure 1(b)). Nuclear densities of the hydrogen atoms of one water molecule (W1 in Figure 1) were elongated, which is consistent with the results of molecular dynamic simulation [2]. The effective usage of MEM to elucidate hydrogen atom positions from neutron powder diffraction data will be discussed together with that of difference Fourier calculations.
Dehydration mechanism of Ciprofloxacin Hydrochloride hydrate crystal
Authors: Putra Okky , Toyoshima Ryosuke , Ibrahim Slamet , Uekusa Hidehiro
Published: November 2015

Active pharmaceutical ingredients (APIs) often exist in different crystalline forms such as hydrate and polymorph, which show different pharmaceutically important physicochemical properties such as crystal color, solubility, stability, dissolution rate and bioavailability. Moreover, crystalline phase transformation is induced by environmental changes such as heating and humidity. Thus, mechanistic investigation based on crystal structures is essential. Ciprofloxacin Hydrochloride (CIP) is fluoroquinolone antimicrobials with potent activity against a broad spectrum of bacteria. From TG/DTA and XRD-DSC measurement, the sesqui-hydrate form dehydrates to anhydrate form I at 140 °C and then transforms to another anhydrate form II at 172 °C. The single crystals of sesqui-hydrate form and anhydrous II were obtained by recrystallization from water and methanol, respectively. However, anhydrate I could not be obtained as single crystal, so the powder crystal form was accomplished by dehydration of hydrate form at 140 °C at vacuum heating condition, and the crystal structure was analyzed by ab-initio powder crystal structure analysis technique using synchrotron X-ray diffraction data. The crystal structure of anhydrous form I was partly related to the hydrate in the packing, i.e., both show one-dimensional chain and two-dimensional sheet structure. However, in anhydrous II, only one-dimensional chain structure was retained. Interestingly, the colors of powder crystal of hydrate and anhydrate I were white, meanwhile, anhydrate II appeared as yellow crystalline powder. The color changes may be explained from their molecular conformation . The torsion angle between flouroquinolone and piperazine of hydrate, anhydrate form I (white) and anhydrate form II (yellow) was 145.71°, 136.28° and 108.65°, respectively. Thus, the large difference in anhydrate II might affect the conjugation in aromatic group slightly and resulted in the color change.
Redefining Solution-Mediated Transformations: Pharmaceutical Systems
Authors: O'Mahony Marcus , Maher Anthony , Croker Denise , Rasmuson Ake , Hodnett Benjamin
Published: November 2015

Engineering the isolation of a metastable or stable crystalline phase of an active pharmaceutical ingredient (API) is of critical importance when crystallizing from solution as an uncontrolled outcome can directly affect API manufacture and performance. The theoretical framework for understanding solution-mediated crystal phase or polymorphic transformation (SMPT) was first established by Cardew & Davey.[1] The process is defined to consist of a metastable phase that dissolves and a stable phase that nucleates and grows independently from the solution. That paper also identified that in terms of a reaction pathway, SMPT could be controlled in either of two ways: by growth of the stable phase or dissolution the metastable phase. Studies concerning SMPT since then have brought the definition and those conclusions into question. Firstly, the recent case of the SMPT from FI to FIII carbamazepine and FII to FIII piractem were studied separately where data on both the solid state composition and solution concentration were collected during the transformation using powder X-ray diffraction and in situ infra-red spectroscopy, respectively. These studies, in combination with a brief review of the literature, reveal that SMPT can be controlled not only in the two ways described by Cardew & Davey but rather in 4 principal ways (Figure 1).[2] Secondly, many studies now identify that nucleation of the stable phase often occurs on the surface of the metastable phase during SMPT [3] and not independently from solution. Again when the literature is examined, this surface supported nucleation event is identified as being either epitaxial in nature or having no or inconclusive evidence of epitaxy. It is concluded that the term "independently" in the definition by Cardew & Davey be redefined to recognize that the crystallization of the stable phase during SMPT is often dependent on the surface of the metastable phase in solution.
Complex Analysis of Counterfeits and New Synthetic Drugs in Forensic Practice
Authors: Kotrly Marek , Roman Michael
Published: November 2015

Counterfeit drugs began to appear on the world market in 90-ies of the 20th century and their number is significantly increasing. It applies not only to dietary (food) supplements, but also for vitally important preparations. The definition of a counterfeit is not entirely uniform, some drugs can be determined in some countries as counterfeits but not in other countries. World Health Organization defines counterfeits as medicines (drugs) "which are deliberately fraudulently mislabelled with respect to identity and/or sources". IFPMA (International Federation of Pharmaceutical Manufacturers Associations) states that 7% of all medicines (drugs, pharmaceuticals) sold around the world are counterfeits and estimates that the value of the trade in counterfeit products is more than USD 30 billion. Forensic analysis deals with these materials comprehensively, besides standard quantitative analysis of content components, examined the shape and form of tablets and logo embossing, measured quantitatively colour, characterized surface, etc. Content substances, in addition to (apart from) techniques of organic analysis, are tested also by methods of X-ray powder diffraction. The advantage is the possibility of non-destructive analysis of tablets directly in the blister and complex analyses of organic and inorganic phases. Automated divergence slits and collimators are use to on a primary x-ray beam. Methods of image analysis are employed for correct adjustment of surface analysed. Phase analysis is carried out using both commercially available databases and as well data of own standards. So-called "Legal Highs" - new synthetic drugs emerging on the world market pose a similarly relevant problem. These are structural variants of known substances with psychomimetic effects, which are not included on the lists of controlled substances. An array of these substances are legally sold not only on the internet, but also in newly established stores called Amsterodam Shops or Smart Shops. Analysis, identification and quantification of these substances are rather complex as they are not included in identification databases. The methods of x-ray diffraction are very suitable complementary techniques to common methods of organic analysis - GC-MS, MS/MS, MSn, NMR, etc. The occurrence of "Legal Highs" on the market can be regarded as very dangerous also considering that toxicity in these substances has not been known so far.
Interpreting Disordered PXRD Structures using Molecular Dynamics
Authors: Johansson Kristoffer , Li Xiaozhou , Bond Andrew , van de Streek Jacco
Published: November 2015

A central topic in the formulation of solid medicinal products is the identification of a suitable solid form of an active compound to obtain optimal physicochemical properties. To this end, disorder may be important for relevant crystal properties like stability. For example, disorder may account for more than 10% of the crystal volume. A rational approach to solid-form selection is typically based on structural information at atomic resolution. In practice, pharmaceutical compounds are not always well-behaved and especially in the study of polymorphs or compounds with flexible groups it can be challenging to obtain crystals suitable for single-crystal X-ray diffraction. Powder X-ray diffraction (PXRD) is a popular alternative, but it generally requires supplementary information like molecular connectivity in simple cases or computational models to solve larger structures. Computational modeling has come a long way and accurate and reliable structures of pharmaceutically relevant compounds can indeed be obtained using laboratory PXRD measurements and quantum-mechanical calculations [1]. The major limitation of quantum mechanical calculations, however, is that they do not consider time nor temperature but only static structures at zero temperature. Thus, these methods cannot model phenomena related to disorder. The molecular dynamics (MD) method can add temperature as well as time and spatial resolution to a model and has in recent years developed to be a scalable, reliable and increasingly available technique. As more and more groups from academia as well as industry employ MD in their work, the development will increase to gain momentum in the coming years. We use MD in a high-performance setting to study crystal properties that are relevant for pharmaceutical research. Using a combination of models from first principles and MD we are able to study highly disordered structures and polymorphs on the basis of PXRD data.
Powder Diffraction study of different forms of Thiocolchicoside
Authors: Delgado J. Miguel , Toro Robert , Diaz de Delgado Graciela
Published: November 2015

It is well-known that the stability, solubility, bioavailability and effectiveness of a pharmaceutical product are affected by the composition (solvates, hydrates, etc.) and the possibility of polymorphism of the Active Pharmaceutical Ingredient (API). In the present study, three different phases of thiocolchicoside, an API used as muscle relaxant, were obtained. The 47 maxima of the X-ray powder diffraction pattern of the raw material were indexed in an orthorhombic unit cell, with a=28.018(7) Å, b=12.519(2) Å, c=8.519(1) Å, V=2988.01 Å3 (M20=56.5; F20=137.6(0.0035,42)) The yellow crystals, obtained after recrystallization of the raw material in water at 370C, produced a pattern with 63 maxima. This pattern was indexed in another orthorhombic unit cell: a=25.264(4) Å, b=13.537(3) Å, c=8.553(1) Å, V=2925.12 Å3 (M20=47.3; F20=131.2 (0.0040, 38)). A third phase was obtained upon heating the yellow crystals. The 51 peaks of its powder pattern are consistent with a monoclinic unit cell with a=17.090(5) Å, b=19.485(5) Å, c=8.526(3) Å, β=100.30(2)0, V=2793.34 Å3 (M20=36.5; F30=56.3 (0.0067, 79)). All the patterns were indexed with DicVOL06 and analyzed with NBS*AIDS83. TGA/DSC analysis showed that the raw material is anhydrous, the yellow crystals are dihydrated, and the third phase is anhydrous. It must be noted that, to our knowledge, these phases have not been reported before. The only entry for a thiocolchicoside-related phase, present in the Powder Diffraction File, corresponds to an ethanol solvate hydrate (PDF 02-073-3591), which is also present in the Cambridge Structural Database (REFCODE: THCLCS). The structure of the hydrated phase was determined, from the powder diffraction data, with TALP[1]. It is worth noting the complexity of the thiocolchicoside molecule, the large number of torsion angles that need to be defined and its potentiality for forming hydrogen bonds (see figure 1).
Applications of XRD in Preformulation and Formulation Studies
Authors: Suryanarayanan Raj
Published: November 2015

Conventionally, XRD has found widespread use for the identification of crystalline solid phases. Recent advances in instrumentation and software extend the utility of the technique to the study of multicomponent systems. Thus the active pharmaceutical ingredient in a complex dosage form, and more importantly, phase transitions induced during processing and storage can be characterized and quantified. The use of an X-ray microdiffractometer with an area detector enabled us to monitor phase transformations in tablets. The spatial information, gained by monitoring the tablet from the surface to the core (depth profiling), revealed progression of phase transformations from the surface to the tablet core as a function of storage time. Low temperature XRD enabled the physical characterization of solutes in frozen aqueous solutions. By attaching a vacuum pump to the low temperature stage of the diffractometer, it was possible to carry out the entire freeze-drying process in situ, in the sample chamber of the XRD. This enabled real time monitoring of phase transitions during all the stages of the freeze-drying process. The use of synchrotron radiation, by substantially enhancing the sensitivity of XRD, has extended the applications of XRD.
Magnetically Oriented Powder Crystal to Indexing and Structure Determination
Authors: Kimura Fumiko , Oshima Wataru , Matsumoto Hiroko , Uekusa Hidehiro , Aburaya Kazuaki , Maeyama Masataka , Kimura Tsunehisa
Published: November 2015

In pharmaceutical sciences, the crystal structure is of primary importance because it influences drug efficacy. Due to difficulties of growing a large single crystal suitable for the single crystal X-ray diffraction analysis, powder diffraction method is widely used. In powder method, two-dimensional diffraction information is projected onto one dimension, which impairs the accuracy of the resulting crystal structure. To overcome this problem, we recently proposed a novel method of fabricating a magnetically oriented microcrystal array (MOMA), a composite in which microcrystals are aligned three-dimensionally in a polymer matrix. The X-ray diffraction of the MOMA is equivalent to that of the corresponding large single crystal, enabling the determination of the crystal lattice parameters and crystal structure of the embedded microcrytals.[1-3] Because we make use of the diamagnetic anisotropy of crystal, those crystals that exhibit small magnetic anisotropy do not take sufficient three-dimensional alignment. However, even for these crystals that only align uniaxially, the determination of the crystal lattice parameters can be easily made compared with the determination by powder diffraction pattern. Once these parameters are determined, crystal structure can be determined by X-ray powder diffraction method. In this paper, we demonstrate possibility of the MOMA method to assist the structure analysis through X-ray powder and single crystal diffraction methods. We applied the MOMA method to various microcrystalline powders including L-alanine, 1,3,5-triphenyl benzene, and cellobiose. The obtained MOMAs exhibited well-resolved diffraction spots, and we succeeded in determination of the crystal lattice parameters and crystal structure analysis.
XRPD to Characterize Disordered and Amorphous Pharmaceutical Samples
Authors: Newman Ann
Published: November 2015

X-ray powder diffraction is commonly used to characterize pharmaceutical samples to identify crystalline forms as well as differentiate crystalline vs amorphous materials. Using XRPD for amorphous materials is usually limited to determining if the materials are fully amorphous or a mixture of crystalline and amorphous materials. Changes in the amorphous halos under various conditions (grinding, drying, water sorption, etc) are usually not investigated, but can give information on the system. This presentation will discuss other uses of XRPD in characterizing amorphous and disordered systems, including amorphous solid dispersions. Patterns involving nanocrystalline, amorphous, and defected samples will be presented and examples on using various methods to obtain further information from the data (pair distribution functions, pure curve resolution methods, diffuse scattering, and Rietveld analysis) will be included.
Magnetic electron density in Fe3O4 examined by RXMS at Fe K edge
Authors: Sasaki Satoshi , Okube Maki , Takayasu Shunichi
Published: November 2015

"It is known that a difference-Fourier synthesis of the Fourier series provides a mean for the location of bonding electrons, by subtracting out the electron density of all atoms in the crystal structure. Here the Fourier technique in X-ray diffraction was applied to observe the magnetic electron density of magnetite Fe3O4. An asymmetrical ratio in the resonant X-ray magnetic scattering (RXMS) provides information on the magnetic moments, which can be estimated from an intensity difference between the right-handed and left-handed polarized X rays. The ratio is proportional to the real part of the product of the spin-contributed structure factor F(hkl) and the complex conjugation of charge-scattered F(hkl). Expanding the equations in difference–Fourier formalization, the spin density can be represented with the observed f""m of RXMS. Synchrotron RXMS experiments were performed at the PF-BL-6C beamline using an AFC-5u four-circle diffractometer. Through a diamond phase retarder the incident X rays were circularly polarized at the Fe K absorption edge, where a wavelength of λ = 1.7439 Å (E = 7.1094 keV) was selected within the pre-edge. A spherical crystal of 0.13 mm in diameter was mounted along the a3 axis with the glass fiber on rare-earth magnet and goniometer head. The intensity data of RXMS were collected for Bragg reflections up to 2θ = 1310. After crystal-structure refinements with scaling of the RXMS data, difference-Fourier syntheses were made in triclinic symmetry with a total of 165 reflections by using the software FRAXY. The syntheses are superior in examining the magnetic effect in the polarization difference and eliminating other effects such as charge scattering, experimental errors and the termination effect. The difference of magnetic electron density between left-handed and right-handed circular polarizations at E was estimated in the Fourier series of partially observed F(hkl). The magnetic electron density on Fourier maps will be discussed in the presentation."
Spin-resolved momentum densities: probing orbitals in magnetic oxides
Authors: Duffy Jonathan
Published: November 2015

Studies of spin-resolved electron momentum densities involve the measurement of the so-called magnetic Compton profile. This is a one-dimensional projection of the electron momentum distribution of only those electrons that contribute to the spin moment of a sample. The technique is applicable to ferri- and ferromagnetic materials. Since electrons originating from different atomic orbitals have specific momentum densities, it is often possible to determine the origin of the magnetism present. Typically, interpretation requires the use of electronic structure calculations using molecular orbital and band structure approaches. The profile is obtained experimentally via the inelastic "Compton" scattering of high energy X-rays. For the experiments discussed here, the high energy beamlines at the ESRF and SPring-8 synchrotron X-ray sources were used, where we have a cryomagnet which can provide a sample environment with applied magnetic fields up to 9 Tesla, at temperatures from 1.3K to 600K. In this talk, we discuss our combined experimental and theoretical study of the spin density of the low-dimensional frustrated metamagnet Ca3Co2O6. The spin moment, measured using magnetic Compton scattering, confirms the existence of a large unquenched Co orbital moment (1.310.1 μB). With regards to the orbital occupation, we have performed molecular orbital calculations on the active trigonal CoO6cluster in order to determine which Co 3d orbitals are responsible for the observed electronic and magnetic behaviour and the observed orbital moment, and revealing the existence a oxygen spin moment of approximately 0.9 μB. Electronic structure calculations with a Hubbard U energy term give Compton profiles which are in good agreement with our experimental data. The magnetic Compton profile exhibits oscillations, which are well described, and their frequency in momentum space corresponds to the real-space inter-cobalt site bond length.
Charge Density Study of two Ni(III) and Ni(II) complexes
Authors: Herich Peter , Fronc Marek , Bučinský Lukáš , Breza Martin , Kožíšek Jozef
Published: November 2015

Experimental charge density of two nickel complexes with oxidation state +3 and +2 of composition (CH3(Ph)3P)+[Ni(bdtCl2)2]-, C31H22Cl4S4P1Ni1 [I] and (CH3(Ph)3P)+[Ni(bdtCl2)2]- dimethylsulfoxide solvate, C25H20Cl2S2P1Ni0.5; C2H6SO [II], (bdtCl2 = 3,6-dichloro-1,2-benzenedithiole ), has been studied. The coordination of Ni central atom by bdtCl2 as a non-innocent ligand gives rise to interesting electronic properties. Compounds I and II crystalize in a monoclinic space groups P 21/c and II in P 21/n, respectively. Their coordination is square-planar with the chromophore [NiS4]. Obvious differences for interatomic distances in metallocycles were found. For I in Ni1-S1-C1-C6-S2-Ni1 there are bond lengths of 2.1534(1), 1.7375(5), 1.4144(8), 1.7327(5), 2.1432(1) Å; and in Ni2-S3-C7-C12-S4-Ni2 there are bond lengths of 2.1453(1), 1.7390(5), 1.4133(7), 1.7387(5), 2.1523(1) Å. For II in Ni1-S1-C1-C6-S2-Ni1 there are bond lengths of 2.1776(2), 1.7437(8), 1.4169(11), 1.7431(8), 2.1663(2) Å. Significantly longer distances for II are in good agreement with the lower oxidation state of central atom. Very accurate data for I an II complexes were obtained with Oxford Diffraction CCD GEMINI R diffractometer at 100K. Multipolar refinement and consecutive topological analysis was performed using XD package. Differences in distribution of electron density in both complexes will be disscussed and compared with quantum-chemical calculations at BP86/VTZP level of theory [1]. This work has been supported by Slovak Grant Agency APVV and VEGA (APVV-0202-10 and 1/0679/11).
Spin Density Distribution in a MOF presenting electric and magnetic order
Authors: Rodriguez-Velamazan J. Alberto , Cañadillas-Delgado Laura , Fabelo Oscar
Published: November 2015

One of the main features of molecular compounds is the possibility of combining different properties in a synergic way giving a multifunctional material. Here we will discuss the case of a compound combining electric and magnetic order, thus giving a "multiferroic" molecular material. The disorder-order of the dimethylammnoium molecule in the Iron(II)-Iron(III) system [NH2(CH3)2]n[FeIIIFeII(HCOO)6]n is in the origin of the observed electric transition from paraelectric to antiferroelectric. In combination with the mentioned electric properties, this compound shows also magnetic order in the form of Nel N-Type ferrimagnetism [1]. The structure of [NH2(CH3)2]n[FeIIIFeII(HCOO)6]n has been characterized by means of neutron diffraction at VIVALDI and D19 instruments at Institut Laue-Langevin (ILL, Grenoble, France), where a crystallographic phase transition was observed from the high temperature structure [P-31c; a =b=8.2550(12) and c=13.891(3) at room temperature] to a lower symmetry one [R-3c; a = b=14.2600(17) and c=41.443(8) at low temperature]. On the other hand, the magnetic behaviour of this compound can be described as a result of two sublattices anti-ferromagnetically coupled, containing different spin carriers FeIII and FeII, respectively, with an ordering temperature of 37 K, and which are responsible of the different magnetic behaviours at low temperature.[2] The different spins of the neighbouring ions [S=5/2 and S=2] result in a ferrimagnetic state. Polarized neutron diffraction measurements aimed at clarifying the spin density map in order to understand the influence of the counter ion in the magnetic properties were carried out at D3 instrument (ILL). Measurements of the flipping ratios were performed with magnetic field of 9 Tesla at 45K, over the magnetic ordering temperature. The results point to an unusual weak spin density located around the counterions which suggests a non-negligible role in the magnetic behavior for the amine group.
Magnetic Excitations in the Kondo Insulator SmB6
Authors: Broholm Collin , Fuhrman Wesley , Leiner Jon , Granroth Garrett , Lumsden Mark , Alekseev P. , Mignot J. , Koohpayeh S. , Cottingham P. , Phelan W. , Schoop L. , Cava R. , McQueen T.
Published: November 2015

SmB6 is a Kondo insulator with surface conductivity that was recently proposed to be topologically protected. I shall describe an inelastic neutron scattering experiment probing magnetic excitations over a wide energy range in a single crystal of SmB6 at low temperatures. Consistent with previous findings by Alekseev et al., a resonant mode near 14 meV is observed at low temperatures near the X and R points of the Brillouin zone. The overall dispersion of the excitation is less than 1 meV. The intensity falls of rapidly in higher Brillouin zones as the 5d electron form factor. The comprehensive inelastic scattering data provide indirect information about the underlying, putative topological, hybridized band structure. Work at IQM was supported by the U.S. Department of Energy, office of Basic Energy Sciences, Division of Materials Sciences and Engineering under Award DE-FG02-08ER46544. Work at ORNL was supported by LDRD 06576.
Computational Pharmaceutical Materials Science: Beyond Static Structures.
Authors: van de Streek Jacco , Johansson Kristoffer , Li Xiaozhou
Published: November 2015

The five Crystal-Structure Prediction (CSP) Blind Tests have shown that molecular-mechanics force fields are not accurate enough for crystal structure prediction[1]. The first--and only--method to successfully predict all four target crystal structures of one of the CSP Blind Tests was dispersion-corrected Density Functional Theory (DFT-D), and this is what we use for our work. However, quantum-mechanical methods (such as DFT-D), are too slow to allow simulations that include the effects of time and temperature, certainly for the size of molecules that are common in pharmaceutical industry. Including the effects of time and temperature therefore still requires molecular dynamics (MD) with less accurate force fields. In order to combine the accuracy of the successful DFT-D method with the speed of a force field to enable molecular dynamics, our group uses Tailor-Made Force Fields (TMFFs) as described by Neumann[2]. In Neumann's TMFF approach, the force field for each chemical compound of interest is parameterised from scratch against reference data from DFT-D calculations; in other words, the TMFF is fitted to mimic the DFT-D energy potential. Parameterising a dedicated force field for each individual compound requires an investment of several weeks, but has the advantage that the resulting force field is more accurate than a transferable force field. Combining crystal-structure prediction with DFT-D followed by molecular dynamics with a tailor-made force field allows us to calculate e.g. the temperature-dependent unit-cell expansion of each predicted polymorph, as well as possible temperature-dependent disorder. This is relevant for example when comparing the calculated X-ray powder diffraction patterns of the predicted crystal structures against experimental data.
Crystal structure prediction of indomethacin
Authors: Li Xiaozhou , Johansson Kristoffer , Bond Andrew , van de Streek Jacco
Published: November 2015

Indomethacin is a non-steroidal anti-inflammatory and antipyretic agent. Because different packing arrangements of the same drug can greatly affect drug properties such as colours, solubility, stability, melting point, dissolution rate and so forth, it is important to predict its polymorphs. The computational prediction of the stable form will reduce undesirable risks in both clinical trials and manufacturing. Reported polymorphs of indomethacin include α, β, γ, δ, ε, η and ζ [1], of which only the thermodynamically stable form γ and the metastable form α are determined. Density functional theory with dispersion-correction (DFT-D) has been used extensively to study molecular crystal structures[2]. It gives better results with a compromise between the computational cost and accuracy towards the reproduction of molecular crystal structures. In the fourth blind test of crystal structure prediction in 2007, the DFT-D method gave a very successful result that predicted all four structures correctly. Rather than using transferable force fields, a dedicated tailor-made force field (TMFF) parameterised by DFT-D calculations[3] is used for every chemical compound. The force field is used to generate a set of crystal structures and delimit a candidate window for energy ranking. The powder diffraction patterns of predicted polymorphs are calculated to compare with experimental data.
Predictive Self-Assembly of Complex Crystals via Building Block Design
Authors: Damasceno Pablo , Engel Michael , Glotzer Sharon
Published: November 2015

A primary challenge for the development of bulk, scalable, and high yield materials with interesting properties is the limited number of structures that can be obtained via self-assembly of nano and micrometer sized particles. Systematic and extensive computational studies of hard polyhedral particles have demonstrated that anisotropy of the building blocks can be a viable route for increasing variability of assembled patterns [1, 2, 3]. Interestingly, the types of structures assembled from this method were shown to be predictable from information contained already in the dense fluid, prior to crystallization. In this talk, the role of such local structures for self-assembly will be rationalized and we will demonstrate how this information can be used as a strategy for design of crystalline and quasicrystalline patterns for both symmetric and asymmetric particles.