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  1. Joanna M. Bąk, Słavomir Domagała, Christian B. Hübschle, Christian Jelsch, Birger Dittrich and Paulina M. Dominiak
    Verification of structural and electrostatic properties obtained by the use of different pseudoatom databases
    Acta Cryst., A67, (2011) 141-153.
    Abstract:
    The existing pseudoatom databases (ELMAM, Invariom, UBDB and ELMAM2) enable structure refinement to be performed with the use of aspherical scattering factors computed from the transferable aspherical atom model (TAAM) as an alternative to independent atom model refinement. In addition, electrostatic properties can be estimated with the help of the databases. The quality of the structural and electrostatic properties obtained from the individual databases was tested. On the basis of a 100 K high-resolution single-crystal X-ray diffraction experiment on L-His-L-Ala dihydrate and 23 K high-resolution data for l-Ala [Destro & Marsh (1988). J. Phys. Chem. 92, 966973], the structural properties, electron-density distributions and molecular electrostatic potentials obtained from different TAAMs were compared to each other and to reference models. Experimental multipolar models and theoretical models refined against theoretical structure factors computed from periodic density functional theory (DFT) calculations were compared to the TAAMs in order to determine which model best describes the crystal-field effect. Unperturbed wavefunctions based on the MP2 and DFT calculations and properties obtained directly from these were used as a reference to judge how properly the databases reproduce the properties of isolated molecules. For Glyl- L-His dihydrate, D, L-His and the above-mentioned two crystal structures, deviations of the molecular dipole moments and Coulombic intermolecular interaction energies from the reference values were examined. Root-mean-square deviations (RMSDs) and correlation coefficients were used as a quantitative measure of the quality of the analysed properties. TAAM refinements reproduce X-H bond lengths optimized in theoretical periodic calculations. Structural properties obtained from different database models are similar to each other. The anisotropic displacement parameters from TAAMs are similar to the results of experimental multipolar refinement; differences are about 0.5 and 2.5% for high-resolution and low-resolution data, respectively. Differences in dipole-moment magnitudes calculated from database models are about 5%, and directions differ by up to 30 degrees. The values of electrostatic interaction energies estimated from the individual TAAMs differ greatly from each other and from the reference values. RMSDs are about 9-15 and 22-33 kJ mol(-1) for UBDB and the other database models, respectively.
    [Full Article - PDF]
  2. C. B. Hübschle and B. Dittrich
    MoleCoolQt - a molecule viewer for charge-density research
    J. Appl. Cryst. 44 (2011). [ doi:10.1107/S0021889810042482 ]
    Abstract:
    MoleCoolQt is a molecule viewer for charge-density research. Features include the visualization of local atomic coordinate systems in multipole refinements based on the Hansen and Coppens formalism as implemented, for example, in the XD suite. Residual peaks and holes from XDfft are translated so that they appear close to the nearest atom of the asymmetric unit. Critical points from a topological analysis of the charge density can also be visualized. As in the program MolIso, color-mapped isosurfaces can be generated with a simple interface. Apart from its visualization features the program interactively helps in assigning local atomic coordinate systems and local symmetry, which can be automatically detected and altered. Dummy atoms - as sometimes required for local atomic coordinate systems - are calculated on demand; XD system files are updated after changes. When using the invariom database, potential scattering factor assignment problems can be resolved by the use of an interactive dialog. The following file formats are supported: XD, MoPro, SHELX, GAUSSIAN (com, FChk, cube), CIF and PDB. MoleCoolQt is written in C++ using the Qt4 library, has a user-friendly graphical user interface, and is available for several flavors of Linux, Windows and MacOS.
    [Full Article - PDF]
  3. B. Dittrich, C. B. Hübschle, J. J. Holstein and F. P. A. Fabbiani
    Towards extracting the charge density from normal-resolution data
    J. Appl. Cryst. 42 (2009), 1110-1121 .
    Abstract:
    The limiting factor for charge-density studies is crystal quality. Although area detection and low temperatures enable redundant data collection, only compounds that form well diffracting single crystals without disorder are amenable to these studies. If thermal motion and electron density rho(r) were deconvoluted, multipole parameters could also be refined with lower-resolution data, such as those commonly collected for macromolecules. Using the invariom database for first refining conventional parameters (x, y, z and atomic displacement parameters), de-convolution can be achieved. In a subsequent least-squares refinement of multipole parameters only, information on the charge density becomes accessible also for data not fulfilling charge-density requirements. A critical aspect of this procedure is the missing information on the correlation between refined and non-refined parameters. This correlation is investigated in detail by comparing a full multipole refinement on high-resolution and a blocked refinement on 'normal-resolution' data sets of ciprofloxacin hexahydrate. Topological properties and dipole moments are shown to be in excellent agreement for the two refinements. A 'normal-resolution' data set of ciprofloxacin hydrochloride 1.4-hydrate is also evaluated in this manner.
    [Full Article - PDF]
  4. B. Dittrich, M. Weber, R. Kalinowski, S. Grabowsky, C. B. Hübschle and P. Luger
    How to easily replace the independent atom model - the example of bergenin, a potential anti-HIV agent of traditional Asian medicine
    Acta Cryst. B65,(2009) 749-756.
    Abstract:
    Bergenin, which has been isolated from a variety of tropical plants, has several pharmacological applications in traditional Asian medicine. Its electron-density distribution was obtained from a room-temperature low-resolution X-ray data set measured with point detection making use of multipole populations from the invariom library. Two refinement models were considered. In a first step, positional parameters and ADPs were refined with fixed library multipoles (model E1). This model was suitable to be input into a second refinement of multipoles (model E2), which converged smoothly although based on Cu K alpha room-temperature data. Quantitative results of a topological analysis of the electron density from both models were compared with Hartree-Fock and density-functional calculations. With respect to the independent atom model (IAM) more information can be extracted from invariom modelling, including the electrostatic potential and hydrogen-bond energies, which are highly useful, especially for biologically active compounds. The reliability of the applied invariom formalism was assessed by a comparison of bond-topological properties of sucrose, for which high-resolution multipole and invariom densities were available. Since a conventional X-ray diffraction experiment using basic equipment was combined with the easy-to-use invariom formalism, the procedure described here for bergenin illustrates how it can be routinely applied in pharmacological research.
    [Full Article - PDF]
  5. Hübschle, C B, Dittrich, B, Grabowsky S, Messerschmidt M and Luger P
    Comparative experimental electron density and electron localization function study of thymidine based on 20 K X-ray diffraction data
    Acta Cryst. B. 64(2008), 363-374.
    Abstract:
    From a high-resolution X-ray data set (sin theta/lambda = 1.1 angstrom(-1)) measured at 20 K the electron-density distribution of the nucleoside thymidine was derived by a classical multipole refinement and by application of the invariom formalism. Owing to the presence of the heteroaromatic thymine ring system two invariom models were compared which considered the nearest and next-nearest neighbors for the invariom assignments. Differences between the two invariom models were small for the bond topological and atomic properties about five times smaller than differences with the classical multipole refinement. Even the latter differences are in the uncertainty ranges which are commonly observed in experimental charge-density work and were found in molecular regions involved in intermolecular contacts. The application of the constrained wavefunction-fitting approach allowed the electron localization function ( ELF) to be obtained from the experimental X-ray data, which was graphically represented and topologically analyzed. ELF basin populations were derived from experiment for the first time. The electron populations in the disynaptic valence basins were related quantitatively to bond orders.
    [Full Article - PDF]
  6. Förster, D, Hübschle, C B,Luger P, Hügle, T and Lentz, D
    On the 2-Electron 3-Center B-H-B Bond: Charge Density Determination of Tetraborane(10) Inorg. Chem. 47 (2008) 1874-1876.
    Abstract:
    In order to characterize the 2-electron 3-center hydride bridges in arachno-tetraborane, an experimental charge-density study was performed complemented with various theoretical calculations. The charge-density distribution and its topological properties were analyzed according to the "atoms in molecules" theory of Bader. The asymmetric bonding situation of the highly polarized hydride bridges is discussed in detail.
    [Full Article - PDF]

  7. R. Kalinowski, B. Dittrich, C. B. Hübschle, C. Paulmann and P. Luger
    Experimental charge density of L-alanyl-L-prolyl-L-alanine hydrate: classical multipole and invariom approach, analysis of intra- and intermolecular topological properties
    Acta Cryst.B63(2007), 753-767.
    Abstract:
    A high-resolution dataset of the tripeptide L-alanyl-L-prolyl-L-alanine hydrate was measured at 100 K using synchrotron radiation and CCD area detection. Electron densities were obtained from a full multipole refinement of the X-ray experimental data, from an invariom transfer and from a theoretical calculation. Topological and atomic properties were derived via an AIM analysis [Atoms in Molecules; see Bader (1990). Atoms in Molecules: A Quantum Theory, No. 22 in International Series of Monographs on Chemistry, 1st ed. Oxford: Clarendon Press] of these densities and compared with each other, as well as with results from the literature of other oligopeptides and amino acids. By application of the invariom formalism to a dataset of limited resolution, its performance was compared with a conventional spherical refinement, highlighting the possibility of aspherically modelling routine structure-determination experiments. The hydrogen-bonding scheme was subject to a detailed analysis according to the criteria of Koch & Popelier [(1995), J. Phys. Chem. 99, 9747-9754] as well as to the characterization of Espinosa et al. [(1998), Chem. Phys. Lett. 285, 170-173; (1999), Acta Cryst. B55, 563-572; (2002), J. Chem. Phys. 117, 5529-5542] using the results from the refined and invariom multipole densities as well as the spherical-density model, which are critically compared.
  8. [Full Article - PDF]

  9. Hübschle, C B, Luger, P and Dittrich, B
    Automation of invariom and of experimental charge density modelling of organic molecules with the preprocessor program InvariomTool
    J. Appl. Cryst. 40(2007), 623–627.
    Abstract:
    The program InvariomTool can be used to obtain high-quality X-ray structures of organic molecules by automating both invariom modelling and the modelling process employed in experimental charge density studies. InvariomTool is a preprocessor program for the XD package [Koritsa´nszky et al. (2003), Technical Report, Freie Universita¨ t Berlin] and allows the analysis of a structure in terms of the local atomic bonding environment in order to assign Hansen–Coppens pseudoatoms that are transferable from one molecule to another (invarioms). It relies on a database of invariom entries, each containing the invariom name, local atomic site symmetry, coordinate system, model-compound name and theoretically predicted multipole population parameters. The information on chemical equivalence and local atomic site symmetry determines which multipole parameters are to be refined in the least-squares procedure of an experimental charge density study. InvariomTool allows the user to generate input files either for invariom refinement, where parameters are fixed and taken from the database, or for an experimental refinement of multipole parameters.

  10. Förster, D Wagner, A, Hübschle, C B, Paulmann, C and Luger, P
    Charge density of L-alanyl-glycyl-L-alanine based on X-ray data collection periods from 4 to 130 hours
    Z. Naturforsch. B. 62 (2007) 696-704.
    Abstract:
    The charge density of the tripeptide L-alanyl-glycyl-L-alanine was determined from three X-ray data sets measured at different experimental setups and under different conditions. Two of the data sets were measured with synchrotron radiation (beamline F1 of Hasylab/DESY, Germany and beamline X10SA of SLS, Paul-Scherer-Institute, Switzerland) at temperatures around 100 K while a third data set was measured under home laboratory conditions (MoK alpha radiation) at a low temperature of 20 K. The multipole refinement strategy to derive the experimental charge density was the same in all cases, so that the obtained charge density properties could directly be compared. While the general analysis of the three data sets suggested a small preference for one of the synchrotron data sets (Hasylab F1), a comparison of topological and atomic properties gave in no case an indication for a preference of any of the three data sets. It follows that even the 4 h data set measured at the SLS performed equally well compared to the data sets of substantially longer exposure time.


  11. Lilianna Checinska, Sergey I. Troyanov, Stefan Mebs, Christian B. Hübschle and Peter Luger
    Examination of intermolecular electronic interactions in the crystal structure of C60(CF3)12 by experimental electron density determination
    Chem. Commun., (2007), 4003–4005.
    Abstract:
    From a high resolution X-ray data set measured at 20 K the experimental electron density of the fullerene C60(CF3)12 was derived and topologically analyzed to yield, in addition to bond topological and atomic properties, information about the density distribution in the region where hexagons of adjacent molecules approach closely at only 3.3 Å.
    [Full Article - PDF]

  12. Christian B. Hübschle, Stephan Scheins, Manuela Weber, Peter Luger, Armin Wagner, Tibor Koritsánszky, Sergey I. Troyanov, Olga V. Boltalina, Il'ya V. Goldt
    Bond Orders and Atomic Properties of the Highly Deformed Halogenated Fullerenes C60F18 and C60Cl30 Derived from their Charge Densities
    Chemistry - A European Journal 13 (2007), 1910-1920.
    Abstract:
    The experimental charge densities of the halogenated C60 fullerenes C60F18 and C60Cl30 were determined from high-resolution X-ray data sets measured with conventional MoKα radiation at 20 K for C60Cl30 and with synchrotron radiation at 92 K for the fluorine compound. Bond topological and atomic properties were analyzed by using Bader's AIM theory. For the different C---C bonds, which vary in lengths between 1.35 and 1.70Å bond orders n between n=2 and significantly below n=1 were calculated from the bond topological properties at the bond critical points (BCP's). The low bond orders are seen for 5/6 bonds with each contributing carbon carrying a halogen atom. By integration over Bader's zero flux basins in the electron density gradient vector field atomic properties were also obtained. In contrast to free C60, in which all carbon atoms have a uniform volume of 11Å3 and zero charge, atomic volumes vary roughly between 5 and 10Å3 in the halogenated compounds. Almost zero atomic charges are also found in the Cl derivative but a charge separation up to ± 0.8 exists between C and F in C60F18 due to the higher fluorine electronegativity, which is also seen in the electrostatic potential for which the electronegativity difference between carbon and fluorine, and the addition to one hemisphere of the fullerene cage leads to a strong potential gradient along the C60F18 molecule. From the summation over all atomic volumes it follows that the halogen addition does not only lead to a dramatic distortion of the C60 cage but also to a significant shrinkage of its volume.
    [Full Article - PDF]

  13. C. B. Hübschle and P. Luger
    MolIso - a program for colour-mapped iso-surfaces
    J. Appl. Cryst. 39(2006), 901-904.
    Abstract:
    The program MolIso allows the visualization of colour-mapped iso-surfaces from XD grid or GAUSSIAN CUBE files. It is written in C++ and uses the OpenGL and GLUT libraries, and is therefore portable. Linux and Windows versions are currently available. Optically correct looking, transparent visualizations are possible. The molecule inside the iso-surface can be depicted as ball-and-stick or atomic displacement parameter ellipsoid-line models. Screenshots can easily be taken in Portable Pix Map format. Short video clips, with various codecs for presentations, are easy to create.
    [Full Article - PDF]

  14. B. Dittrich, C. B. Hübschle, P. Luger and M. A. Spackman
    Introduction and validation of an invariom database for amino-acid, peptide and protein molecules
    Acta Cryst. D62(2006), 1325-1335.
    Abstract:
    A database of invarioms for structural refinement of amino-acid, oligopeptide and protein molecules is presented. The spherical scattering factors of the independent atom or promolecule model are replaced by `individual' aspherical scattering factors that take into account the chemical environment of a bonded atom. All amino acids were analysed in terms of their invariom fragments. In order to generate 73 database entries that cover this class of compounds, 37 model compounds were geometry-optimized and theoretical structure factors were calculated. Multipole refinements were then performed on these theoretical structure factors to yield the invariom database. Validation of this database on an extensive number of experimental small-molecule crystal structures of varying quality and resolution shows that invariom modelling improves various figures of merit. Differences in figures of merit between invariom and promolecule models give insight into the importance of disorder for future protein-invariom refinements. The suitability of structural data for application of invarioms can be predicted by Cruickshank's diffraction-component precision index [Cruickshank (1999), Acta Cryst. D55, 583-601].
    [Full Article - PDF]

  15. R. Kingsford-Adaboh, B. Dittrich, C.B. Hübschle, W.S.K. Gbewonyo, H. Okamoto, M. Kimura and H. Ishida
    Invariom structure refinement, electrostatic potential and toxicity of 4-O-methylalpinumisoflavone, O,O-dimethylalpinumisoflavone and 5-O-methyl-4-O-(3-methylbut-2-en-1-yl)alpinum-isoflavone
    Acta Cryst. B62(2006), 843-849.
    Abstract:
    The accurate X-ray single-crystal structures of the isoflavone compounds 4-O-methylalpinumisoflavone, O,O-dimethylalpinumisoflavone and 5-O-methyl-4-O-(3-methylbut-2-en-1-yl)alpinumisoflavone { alpinumisoflavone = 5-hydroxy-7-( 4-hydroxyphenyl )-2,2-dimethyl-2H,6H-benzo [1,2-b:5,4-b'] dipyran-6-one } from data sets measured at cryogenic temperature have been obtained from invariom modelling using theoretically predicted Hansen and Coppens multipole-model form factors, which describe the aspherical electron density distribution. Molecular dipole moments and electrostatic potentials obtained from invariom modelling are discussed and compared with results from ab initio theoretical calculations. All three studied compounds are solvent extracts of root bark or seed powder of Millettia thonningii (leguminosae), a plant molluscicide and cercaricide used in Franco West Africa as medication against various diseases. The compounds' toxicities to brine shrimp have been determined and their different potencies tentatively related to conformation differences, intramolecular contacts, dipole moments and electrostatic potential features.
    [Full Article - PDF]

  16. L. Checinska, S. Mebs, C.B. Hübschle, D. Forster, W. Morgenroth and P. Luger
    Reproducibility and transferability of topological data: experimental charge density study of two modifications of L-alanyl-L-tyrosyl-L-alanine
    Org. Biomol. Chem. 4(2006), 3242-3251.
    Abstract:
    Two crystalline modi. cations of the tripeptide L-Ala -L-Tyr-L-Ala, which have different solvent molecules in the crystal structure ( water and ethanol for modi. cations 1 and 2), were the subject of experimental charge density studies based on high resolution X-ray data collected at ultra-low temperatures of 9 K ( 1) and 20 K ( 2), respectively. The molecular structures and the intermolecular interactions were found to be rather similar in the two crystal lattices, so that this study allowed the reproducibility of the charge density of a given molecule in different ( but widely comparable) crystalline environments to be examined. With respect to bond topological and atomic properties, the agreement between the two modi. cations of the title tripeptide was in the same range as found from the comparison with the previously reported results of tri-L-alanine. It follows that the reproducibility and transferability of quantitative topological data are comparable and that within the accuracy of experimental charge density work the replacement of the central amino acid residue L-Ala by L-Tyr has no significant influence, neither on bond nor on the atomic properties of the oligopeptide main chain. Intermolecular interactions in the form of hydrogen bonds were characterized quantitatively and qualitatively by topological criteria and by mapping the charge density distribution on the Hirshfeld surface.
    [Full Article - PDF]

  17. P. Luger, A. Wagner, Ch. B. Hübschle, S. I. Troyanov:
    Experimental Advances for High Speed Evaluation of Electron Densities.
    J. Phys. Chem. A109(2005), 10177-10179.
    Abstract:
    Evaluating electron densities of entire classes of chemically or biologically related compounds is within reach thanks to advances in high-speed high-resolution synchrotron diffraction: a 12 h sequence of diffraction experiments has been conducted at the beamline X10SA of the Swiss Light Source (SLS). It resulted in four high-resolution X-ray data sets used for experimental electron density determinations of the two halogenated fullerenes C60F18 and C60Cl30, the Watson and Crick base pair adenine-thymine and the tripeptide L-Ala-Gly-L-Ala. Application is considered relevant for life sciences where the study of structure-guided biological recognition processes can now be completed by electronic information of entire series of molecules.
    [Full Article - PDF]

  18. B. Dittrich, C.B. Hübschle, M. Messerschmidt, R. Kalinowski, D. Girnt, P.Luger:
    The Invariom Model and its Application: Refinement of D,L-Serine at Different Temperatures and Resolution.
    Acta Crystallogr. A61(2005), 314 - 320.
    Abstract:
    Three X-ray data sets of the same D,L-serine crystal were measured at temperatures of 298, 100 and 20 K. These data were then evaluated using invarioms and the Hansen & Coppens aspherical-atom model. Multipole populations for invarioms, which are pseudoatoms that remain approximately invariant in an intermolecular transfer, were theoretically predicted using different density functional theorem (DFT) basis sets. The invariom parameters were kept fixed and positional and thermal parameters were refined to compare the fitting against the multi-temperature data at different resolutions. The deconvolution of thermal motion and electron density with respect to data resolution was studied by application of the Hirshfeld test. Above a resolution of sin(theta/lambda) = 0 A-1 or d = 0.9 A, this test was fulfilled. When the Hirshfeld test is fulfilled, a successful modeling of the aspherical electron density with invarioms is achieved, which was proven by Fourier methods. Molecular geometry improves, especially for H atoms, when using the invariom method compared to the independent-atom model, as a comparison with neutron data shows. Based on this example, the general applicability of the invariom concept to organic molecules is proven and the aspherical density modeling of a larger biomacromolecule is within reach.
    [Full Article - PDF]

  19. Christian B. Hübschle, Marc Messerschmidt, Dieter Lentz und Peter Luger
    Neubestimmung der Ladungsdichte und topologische Analyse von beta-Diboran bei 94K.
    Z. Anorg. Allg. Chem. 630 (2004) 1313-1316.
    Inhaltsübersicht.
    Die experimentelle Ladungsdichte von beta-Diboran wurde aus 1779 Reflexen neu bestimmt, die bis (sin(theta)/lambda) = 1.11-1 mit MoKalpha-Strahlung und CCDFlächendetektion bei 94(1) K gemessen wurden. Im Gradientenvektorfeld der Elektronendichte wurden die stark gebogenen Bindungspfade der B-HmuBindungen verifiziert. Eine topologische Analyse ergab in Übereinstimmung mit theoretischen Ergebnissen keinen Hinweis auf einen bindungskritischen Punkt zwischen den beiden Boratomen.
    [Full Article - PDF]

  20. Ch. B. Hübschle, M. Messerschmidt, and P. Luger
    Crystal structure of DL-Tryptophan at 173K
    Cryst. Res. Technol. 39, No. 3, (2004) 274-278.
    Abstract:
    The crystal structure of pure DL-tryptophan has been determined at 173 K, using large but thin plate formed crystals of C11H12N2O2, which were grown by cooling down a saturated solution of DL-tryptophan in isopropanole / formic acid. The crystals are monoclinic, space group P 21/c, with the unit cell constants: a = 18.899(2), b = 5.7445(6), c = 9.309(1) Angstrom, beta² = 101.776(2), V = 989.4(4) , Dcalc = 1.371, Z = 4, F(000) = 432,(MoKalpha) = 0.71073 Angstrom, muµ = 0.096 mm-1. The crystal structure was solved by direct methods and refined by full-matrix least squares to a final R-factor = 4.03 % with 3343 unique reflections of which 2104 were observed. The molecule is zwitterionic in the crystal with the protonated amino group and the carboxylate group in unusual conformations with respect to the indole ring system compared to other tryptophan derivatives. A D- and L- molecular pair forms a dimer by N---H...O hydrogen bonds via a crystallographic inversion center. The dimers are linked by further N---H...O hydrogen bonds to form a head to head bilayer arrangement of the molecules in the crystal lattice. Except for weak van der Waals contacts there is no relation between indole tails of neighboured bilayers.
    [Full Article - PDF]

  21. Christian B. Hübschle, Birger Dittrich and Luger, Peter
    L-Tryptophan formic acid solvate at 183 K
    Acta Cryst. C58 (2002), S. 540-542.
    Abstract:
    In the title compound, C11H12N2O2·CH2O2, at 183 K. L-tryptophan appears in the zwitterionic form, while the formic acid molecule is neutral. The formic acid molecule is the donor in a strong O-HO hydrogen bond to the carboxylate group of the tryptophan molecule, with a short H-O contact of 2.487 (2) .
    [Full Article - PDF]

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