Ab Initio Determination Research Articles

Facile production of minor metabolites for drug development using a CYP3A shuffled library

Metabolic profiling of new drugs is limited by the difficulty in obtaining sufficient quantities of minor metabolites for definitive structural identification. Biocatalytic methods offer the potential to produce metabolites that are difficult to synthesize by traditional medicinal chemistry. We hypothesized that the regioselectivity of the drug metabolizing cytochrome P450s could be altered by directed evolution to produce minor metabolites of drugs in development. A biocatalyst library was constructed by DNA shuffling of four CYP3A forms. The library contained 11±4 (mean±SD) recombinations and 1±1 spontaneous mutations per mutant. On expression in Escherichia coli, 96% of mutants showed detectable activity to at least one probe substrate. Using testosterone as a model drug-like substrate, mutants were found that preferentially formed metabolites produced in only trace amounts by parental forms. A single 1.6 L batch culture of one such mutant enabled the facile isolation of 0.3 mg of the minor metabolite 1β-hydroxytestosterone and its ab initio structural determination by 1D- and 2D-NMR spectroscopy.

Ab initio study of II–(VI)2 dichalcogenides

The structural stabilities of the (Zn,Cd)(S,Se,Te)2 dichalcogenides have been determined ab initio. These compounds are shown to be stable in the pyrite phase, in agreement with available experiments. Structural parameters for the ZnTe2 pyrite semiconductor compound proposed here are presented. The opto-electronic properties of these dichalcogenide compounds have been calculated using quasiparticle GW theory. Bandgaps, band structures and effective masses are proposed as well as absorption coefficients and refraction indices. The compounds are all indirect semiconductors with very flat conduction band dispersion and high absorption coefficients. The work functions and surface properties are predicted. The Te and Se based compounds could be of interest as absorber materials in photovoltaic applications.

Ab Initio determination of Cu 3d orbital energies in layered copper oxides

It has long been argued that the minimal model to describe the low-energy physics of the high Tc superconducting cuprates must include copper states of other symmetries besides the canonical one, in particular the orbital. Experimental and theoretical estimates of the energy splitting of these states vary widely. With a novel ab initio quantum chemical computational scheme we determine these energies for a range of copper-oxides and -oxychlorides, determine trends with the apical Cu–ligand distances and find excellent agreement with recent Resonant Inelastic X-ray Scattering measurements, available for La2CuO4, Sr2CuO2Cl2, and CaCuO2.

Structural and physical properties of the new intermetallic compound Yb 3Pd 2Sn 2

The crystal structure of the ternary intermetallic compound Yb 3Pd 2Sn 2 has been determined ab initio from powder X-ray diffraction data. The compound crystallizes as a new structure type in the orthorhombic space group Pbcm and lattice constants a=0.58262(3), b=1.68393(8), c=1.38735(7) nm. Yb 3Pd 2Sn 2 is composed of a complex ∞[Pd 2Sn 2] δ− polyanionic network in which the Yb ions are embedded. A comparison between this structure and those of Eu 3Pd 2Sn 2 and Ca 3Pd 2Sn 2, other novel polar intermetallic compounds, was made. DC susceptibility and 170Yb Mössbauer spectroscopic measurements indicate a close-to divalent Yb behavior. Moreover, a hybridization between 4 f and conduction electrons is suggested by electronic structure calculations and heat capacity measurements.

Calculations of the thermophysical properties of binary mixtures of noble gases at low density from ab initio potentials

Interaction potentials determined ab initio from quantum mechanics were used to calculate the thermophysical properties of six binary mixtures of noble gases: helium–neon, helium–argon, helium–krypton, neon–argon, neon–krypton and argon–krypton. From the ab initio potentials, the second pressure virial coefficient, the binary diffusion coefficient and the thermal diffusion factor were computed for the considered binary mixtures at low density in the temperature range 100–5000 K employing well-established formulas in statistical thermodynamics and the kinetic theory of dilute gases. In all cases, while not as good as that for pure noble gases, close agreement between experimental data and the theoretically calculated values shows that ab initio potentials are reliable for the calculation of accurate thermophysical properties of binary mixtures of noble gases over a wide temperature range.

Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs

Commercial and recrystallized polycrystalline samples of carprofen, a nonsteroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural techniques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the construction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P2(1) /c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I → II is isostructural. Polymorphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods.

Electrostatic Damping Functions and the Penetration Energy

The use of damping functions to correct the multipole expansion at short-range is explored. Damping functions for the terms in the multipole expansion can be determined ab initio as a linear combination of analytic functions of the separation between sites, but there are additional short-range terms that have different angular dependence. The approach provides a detailed ab initio description of the penetration energy correction to the multipole expansion in an easily comprehensible form.

The vibrational spectrum of the water dimer: Comparison between anharmonic ab initio calculations and neon matrix infrared data between 14,000 and 90 cm −1

The infrared spectrum of the water dimer trapped in solid neon has been recorded up to the visible by improving significantly the experimental technique used in a previous paper [Y. Bouteiller, J.P. Perchard, Chem. Phys. 305 (2004) 1]. A total of 22 intramolecular transitions of the proton donor (PD) and 23 of the proton acceptor (PA) are now identified and assigned on the basis of 16O/ 18O isotopic shifts and of realistic anharmonicity corrections. From an ab initio determination of the potential energy a perturbation-resonance treatment has been carried out for each polyad P n , n = 2–8. Finally combinations of intra + intermolecular transitions were identified and assigned on the basis of calculated anharmonicity coefficients.

Analysis of phases in the structure determination of an icosahedral virus.

The constraints imposed on structure-factor phases by noncrystallographic symmetry (NCS) allow phase improvement, phase extension to higher resolution and hence ab initio phase determination. The more numerous the NCS redundancy and the greater the volume used for solvent flattening, the greater the power for phase determination. In a case analyzed here the icosahedral NCS phasing appeared to have broken down, although later successful phase extension was possible when the envelope around the NCS region was tightened. The phases from the failed phase-determination attempt fell into four classes, all of which satisfied the NCS constraints. These four classes corresponded to the correct solution, opposite enantiomorph, Babinet inversion and opposite enantiomorph with Babinet inversion. These incorrect solutions can be seeded from structure factors belonging to reciprocal-space volumes that lie close to icosahedral NCS axes where the structure amplitudes tend to be large and the phases tend to be 0 or π. Furthermore, the false solutions can spread more easily if there are large errors in defining the envelope designating the region in which NCS averaging is performed.

Photorearrangements in spiro-conjoined cyclohexa-2,5-dien-1-one

The unexpected formation of cyclohexa-2,5-dien-1-one ( 6) spiro-conjoined with a dihydrobenzofuran framework, and the photochemical behavior of this compound in solution as well as in the solid state are described. The photoreaction of 6 in solution affords two rearranged products, one ( 7) accompanied by the enlargement of the oxygen heterocyclic ring and the other ( 8) accompanied by cyclopentadienone fragmentation. In the solid state, the former is the sole photoproduct of both solvated and desolvated crystals. The desolvated crystals were obtained as polycrystalline solids by thermal release of solvent molecules, and its structure was elucidated by ab initio determination from X-ray powder diffraction data followed by the Rietveld refinement.

Structure analysis of titanate nanorods by automated electron diffraction tomography

A hitherto unknown phase of sodium titanate, NaTi(3)O(6)(OH)·2H(2)O, was identified as the intermediate species in the synthesis of TiO(2) nanorods. This new phase, prepared as nanorods, was investigated by electron diffraction, X-ray powder diffraction, thermogravimetric analysis and high-resolution transmission electron microscopy. The structure was determined ab initio using electron diffraction data collected by the recently developed automated diffraction tomography technique. NaTi(3)O(6)(OH)·2H(2)O crystallizes in the monoclinic space group C2/m. Corrugated layers of corner- and edge-sharing distorted TiO(6) octahedra are intercalated with Na(+) and water of crystallization. The nanorods are typically affected by pervasive defects, such as mutual layer shifts, that produce diffraction streaks along c*. In addition, edge dislocations were observed in HRTEM images.

Electronic structure and equation of state of PdO 2 from ab initio

The electronic band structure and chemical bonding properties of rutile type PdO 2 are calculated in the context of the difficulties encountered for its synthesis. They are provided based on ab initio determination of the lattice parameters and energy–volume equation of state leading to a metallic behavior within the ground state rutile structure.

ERS-18: A new member of the NON–EUO–NES zeolite family

ERS-18, a new small pore high silica zeolite, was synthesized using 6-azonia-spiro-[5,5]-undecane hydroxide as structure directing agent. Its crystal structure was determined ab initio by using high-resolution synchrotron X-ray powder diffraction data and the zeolite-dedicated software FOCUS. ERS-18 shows orthorhombic symmetry (s.g. F mmm) setting with unit cell parameters: a = 34.989, b = 13.667 and c = 22.559 Å. The values of b and c parameters are in common with zeolites of the NON–EUO–NES family (IZA codes for nonasil, EU-1, and NU-87, respectively); within this group the a parameter, corresponding to the layer stacking direction, varies from ∼15.0 (NON) to ∼20.0 (EUO), to ∼25.0 Å (NES). Therefore, ERS-18 can be regarded as a new member of this family having the longest stacking parameter (i.e. ∼35.0 Å) reported so far. The ERS-18 framework is characterized by the presence of 8-ring channels (crystallographic free dimensions: 3.1 × 2.5 Å) running along the [0 1 0] direction and supercages delimited by 12-rings (crystallographic free dimensions: 6.1 × 5.2 Å, cross section; 18.4 Å, depth) aligned along [1 0 0] and off the 8-ring channels.

Ab initio determination of atomic structure and energy of surface states of bare and hydrogen covered GaN (0001) surface — Existence of the Surface States Stark Effect (SSSE)

Density Functional Theory (DFT) calculations indicate that energetically stable structure of clean GaN(0001) surface posses (2 × 1) reconstruction, having every second row of Ga located near plane of N atoms, that gives rise to Ga-related dispersionless surface electronic state, already identified by angle resolved photoelectron spectroscopy (ARPES) measurements [S.S. Dhesi et al. Phys. Rev. B 56 (1997) 10271, L. Plucinski et al. Surf. Sci 507-10 (2002) 223, S. M. Widstrand et al. Surf. Sci. 584 (2005) 169]. The energy reduction in reconstruction proceeds via change of the hybridization of the occupied Ga surface states from sp 3 to sp 2, transforming the empty states to p z type. It is also shown that the electric subsurface field, modeled in new slab model which allows to simulate electric fields at the semiconductor surfaces [P. Kempisty et al., J. Appl. Phys. 106 (2009) 054901], strongly affects the energy of electronic states of GaN(0001) surfaces. The change of the field may shift the energy of surface states of bare and hydrogen covered GaN(0001) surface, by several eV with respect to the band states. The phenomenon, denoted as Surface States Stark Effect (SSSE), explains various band bending values, measured at differently doped n-type GaN(0001) surfaces. It is shown also that, for the adsorbate density up to one H atom for each Ga surface atom i.e. 1 monolayer coverage (1 ML), the hydrogen adatoms are located at the on-top positions, i.e. directly above Ga atoms. For these adsorbate densities, the H-related quantum surface state is located slightly below the valence band maximum (VBM) in the case of p-type GaN surface. For n-type GaN, the H-related surface state is located deeply in the valence band, about 2 eV below VBM. For higher, 1.25 ML hydrogen coverage, the two H adatoms create either surface attached H 2 ad-molecule (energetically stable) or triple bridge configuration is created (metastable). The H 2 ad-molecule is weekly attached to the surface, having the desorption energy barrier equal to 0.16 eV. For 1.25 ML coverage the DFT results were obtained for p-type GaN only. They show that in the ad-molecule case, a new surface electronic state arises which is located about 6.7 eV below VBM. In the case of the bridge configuration, the bridge related surface state is located closely to the conduction band minimum (CBM).

新しいＡｂ Ｉｎｉｔｉｏ粉末構造解析法の開発

Genetic Algorithm (GA) applied to ab initio structure determination from synchrotron powder diffraction is described. It seems to have an advantage over other real space methods for ab initio structure determination because of the existence of schema theorem. As an example, the case of Prednisolone Succinate is shown in some detail. Future development of GA in crystallography is briefly described.

Crystal structure determination by global optimisation in configuration space: a case study for distributed computing on the NRW-grid

The problem of ab-initio crystal structure determination from (incomplete) powder X-ray diffraction data is formulated as a global optimisation problem. The problem is of complexity class P, which suggests that the problem itself is practically infeasible for any but trivial structures. Yet, we show in this report that the inherent symmetry of the problem along with suitable heuristics and with massive computational power, allows the determination of structures with up to 20 atoms in the asymmetric unit from scratch. We give an overview of the methods employed and show numerical examples obtained by solving a model problem on the NRW-grid, which harnesses the computational power of several hundred computers at several universities in the state of Northrhine-Westfalia.

Modeling van der Waals interactions between proteins and inorganic surfaces from time-dependent density functional theory calculations

In this work we show how the ab initio determination of van der Waals coefficients within time-dependent density functional theory can be used to build efficient and accurate atomistic models that describe the long-range interactions of proteins with other proteins and of proteins with semi-conducting surfaces. The model parameters are fitted so that they reproduce the ab initio van der Waals coefficients of amino acids and dipeptides. We then assess the quality of our results by comparing ab initio van der Waals coefficients for larger peptides with the coefficients yielded by the models. The different sets of parameters can be easily incorporated in current empirical force field methods, thus providing an essential ingredient for molecular dynamics simulations of proteins close to surfaces.

Periodic ab initio estimates of the dispersive interaction between molecular nitrogen and a monolayer of hexagonal BN

The ab initio determination of the leading long-range term of pairwise additive dispersive interactions, based on the independent analysis of the response properties of the interacting objects, is here considered in the case where these are part of a periodic system. The interaction of a nitrogen molecule with a thin film of hexagonal BN has been chosen as a case study for identifying some of the problems involved, and for proposing techniques for their solution. In order to validate the results so obtained, the interaction energy between N(2) and a BN monolayer at different distances has been estimated following a totally different approach, namely by performing post-Hartree-Fock (MP2) supercell calculations using the Crystal+Cryscor suite of programs. The results obtained with the two approaches closely agree over a long range, while the limit of validity of the purely dispersive regime can be clearly assessed.

Two crystal forms of cis-bis(ethylamine) dichloro platinum(II)

Cis-bis(ethylamine) dichloro platinum(II) (form A) was prepared by a reaction of K 2PtCl 4 with CH 3CH 2NH 2*HCl and CH 3COOK. Form B was obtained from A after recrystallization from a solution of dimethylformamide in HCl. Ab initio crystal structure determination was carried out for both forms using X-ray powder diffraction techniques. The forms A and B are rather similar from the structural point of view. The crystal structures consist of discrete asymmetric molecules with a platinum atom in the planar coordination. Ethyl groups orient towards both sides of the platinum coordination plane. The molecules are packed in layers. Form A differs from B by а smaller cell volume by c.a. 51 Å 3. The observed distinction is the result of molecular conformations. IR- and 1H, 13C, 15N MAS NMR spectroscopy’s support the differences in ethylamine conformation for both forms. Thermal decomposition begins for form A at 180 °C whereas for form B it is 10 °C higher, resulting in the formation of Pt metal. The interpretation based on structural features supposes that the acidic media during the recrystallization suppresses hydrogen (Cl···H–N) bonding within cis-[Pt(CH 3CH 2NH 2) 2Cl 2] molecules and causes more extensive intermolecular H-bonding which results in bigger volume and higher thermal stability.

Ab Initio Determination of Ground and Excited State Oxidation Potentials of Organic Chromophores for Dye-Sensitized Solar Cells

Ab initio calculations of the ground state oxidation potential (GSOP) and excited state oxidation potential (ESOP) are reported for a set of four triphenylamine-based dyes for dye-sensitized solar cell (DSSC) applications, with increasing degree of charge transfer. The performance of DFT in predicting GSOP is evaluated by employing various exchange-correlation (x-c) functionals, with different amounts of Hartree−Fock exchange and different combinations of correlation functionals. The choice of the correlation part of the x-c functional was crucial in getting accurate GSOPs. For excited state geometry optimizations, needed to calculate the adiabatic excitation energies E0−0 and therefore the ESOPs, the use of hybrid functionals with a large amount (∼50%) of nonlocal Hartree−Fock exchange has been shown to be mandatory to avoid the formation of artificial minima in correspondence of a twisted geometries with a high degree of charge transfer. Our results show that a proper DFT/TDDFT approach can provide a re...