Probable Orientation Research Articles

TALP: a multisolution direct-space strategy for solving molecular crystals from powder diffraction data based on restrained least squares

TALP is a new direct-space strategy forab initiocrystal structure determination of molecular crystals from powder diffraction data. The strategy is based on a preliminary exploration stage, which considers atomic overlap, followed by a subsequent stage of local incremental scans, both coupled to fast restrained least-squares minimizations with the atomic coordinates as refined parameters. The observed intensities are extracted from the powder pattern by a three-step procedure [Vallcorba, Rius, Frontera, Peral & Miravitlles (2012).J. Appl. Cryst.45, 844–848], and the molecular model and distance restraints are derived from molecular mechanics calculations or from similar reported structures. The solution process consists of several independent trials, each one resulting in a crystal structure proposal with an associated figure of merit. TALP has been tested on laboratory X-ray powder diffraction data of 14 molecular compounds of known crystal structure and of variable complexity. In most cases, the crystal structure is solved in a short time (less than an hour), even for calculated models. For the most complex structures (e.g.13 torsion angles), the general scan is assisted by a rotation function, which provides a ranked list of most probable model orientations. In this way only the positional and conformation parameters need to be explored.

Exploiting spatial descriptions in visual scene analysis

The reliable automatic visual recognition of indoor scenes with complex object constellations using only sensor data is a nontrivial problem. In order to improve the construction of an accurate semantic 3D model of an indoor scene, we exploit human-produced verbal descriptions of the relative location of pairs of objects. This requires the ability to deal with different spatial reference frames (RF) that humans use interchangeably. In German, both the intrinsic and relative RF are used frequently, which often leads to ambiguities in referential communication. We assume that there are certain regularities that help in specific contexts. In a first experiment, we investigated how speakers of German describe spatial relationships between different pieces of furniture. This gave us important information about the distribution of the RFs used for furniture-predicate combinations, and by implication also about the preferred spatial predicate. The results of this experiment are compiled into a computational model that extracts partial orderings of spatial arrangements between furniture items from verbal descriptions. In the implemented system, the visual scene is initially scanned by a 3D camera system. From the 3D point cloud, we extract point clusters that suggest the presence of certain furniture objects. We then integrate the partial orderings extracted from the verbal utterances incrementally and cumulatively with the estimated probabilities about the identity and location of objects in the scene, and also estimate the probable orientation of the objects. This allows the system to significantly improve both the accuracy and richness of its visual scene representation.

Orientation selective DEER measurements on vinculin tail at X-band frequencies reveal spin label orientations

Double electron electron resonance (DEER) spectroscopy has been established as a valuable method to determine distances between spin labels bound to protein molecules. Caused by selective excitation of molecular orientations DEER primary data also depend on the mutual orientation of the spin labels. For a doubly spin labeled variant of the cytoskeletal protein vinculin tail strong orientation selection can be observed already at X-band frequencies, which allows us to reduce the problem to the relative orientation of two molecular axes and the spin–spin axis parameterized by three angles. A full grid search of parameter space reveals that the DEER experiment introduces parameter-space symmetry higher than the symmetry of the spin Hamiltonian. Thus, the number of equivalent parameter sets is twice as large as expected and the relative orientation of the two spin labels is ambiguous. Except for this inherent ambiguity the most probable relative orientation of the two spin labels can be determined with good confidence and moderate uncertainty by global fitting of a set of five DEER experiments at different offsets between pump and observer frequency. The experiment provides restraints on the angles between the z axis of the nitroxide molecular frame and the spin–spin vector and on the dihedral between the two z axes. When using the same type of label at both sites, assignment of the angle restraints is ambiguous and the sign of the dihedral restraint is also ambiguous.

Redox, mutagenic and structural studies of the glutaredoxin/arsenate reductase couple from the cyanobacterium Synechocystis sp. PCC 6803

The arsenate reductase from the cyanobacterium Synechocystis sp. PCC 6803 has been characterized in terms of the redox properties of its cysteine residues and their role in the reaction catalyzed by the enzyme. Of the five cysteines present in the enzyme, two (Cys13 and Cys35) have been shown not to be required for catalysis, while Cys8, Cys80 and Cys82 have been shown to be essential. The as-isolated enzyme contains a single disulfide, formed between Cys80 and Cys82, with an oxidation–reduction midpoint potential (Em) value of −165mV at pH 7.0. It has been shown that Cys15 is the only one of the four cysteines present in Synechocystis sp. PCC 6803 glutaredoxin A required for its ability to serve as an electron donor to arsenate reductase, while the other three cysteines (Cys18, Cys36 and Cys70) play no role. Glutaredoxin A has been shown to contain a single redox-active disulfide/dithiol couple, with a two-electron, Em value of −220mV at pH 7.0. One cysteine in this disulfide/dithiol couple has been shown to undergo glutathionylation. An X-ray crystal structure, at 1.8Å resolution, has been obtained for glutaredoxin A. The probable orientations of arsenate reductase disulfide bonds present in the resting enzyme and in a likely reaction intermediate of the enzyme have been examined by in silico modeling, as has the surface environment of arsenate reductase in the vicinity of Cys8, the likely site for the initial reaction between arsenate and the enzyme.

Molecular docking analysis of novel Non-Nucleoside Reverse Transcriptase Inhibitors in development: implication for rational drug design

Background Human immunodeficiency virus (HIV) from a family of retroviruses is a causative organism for acquired immuno deficiency syndrome (AIDS), affecting more than 40 million people worldwide [1]. Reverse transcription of the HIV single-stranded RNA genome into double-stranded DNA is one of the essential key step in the virus replication life-cycle and acts as lucrative target for drug action. Till date, out of 20 anti-HIV drugs approved for the treatment of HIV infection, eleven approved anti-HIV drugs target RT, and encompass three classes of agents that inhibit RT by different mechanisms (Nucleoside Reverse Transcriptase Inhibitors, NRTIs; Non-Nucleoside Reverse Transcriptase Inhibitors, NNRTIs; Nucleotide Reverse Transcriptase Inhibitors, NtRTIs) [2]. The NNRTIs serve as an increasingly important role in the therapy of HIV infection, due to their unique antiviral potency, high specificity and low toxicity. Present work illustrates the probable binding affinity, interatomic contacts and orientation of novel of NNRTIs in development at the allosteric site of the HIV-RT through an iterative computational process and molecular docking to explicate the necessary structural requirement for rational drug design.

Kinetic Characterisation of Phosphofructokinase Purified fromSetaria cervi: A Bovine Filarial Parasite

Phosphofructokinase (PFK), a regulatory enzyme in glycolytic pathway, has been purified to electrophoretic homogeneity from adult female Setaria cervi and partially characterized. For this enzyme, the Lineweaver-Burk's double reciprocal plots of initial rates and D-fructose-6-phosphate (F-6-P) or Mg-ATP concentrations for varying values of cosubstrate concentration gave intersecting lines indicating that K m values for F-6-P (1.05 mM) and ATP (3 μM) were independent of each other. S. cervi PFK, when assayed at inhibitory concentration of ATP (>0.1 mM), exhibited sigmoidal behavior towards binding with F-6-P with a Hill coefficient (n) value equal to 1.8 and 1.7 at 1.0 and 0.33 mM ATP, respectively. D-fructose-1,6-diphosphate (FDP) competitively inhibited the filarial enzyme: K i and Hill coefficient values being 0.18 μM and 2.0, respectively. Phosphoenolpyruvate (PEP) also inhibited the enzyme competitively with the K i value equal to 0.8 mM. The Hill coefficient values (>1.5) for F-6-P (at inhibitory concentration of ATP) and FDP suggested its positive cooperative kinetics towards F-6-P and FDP, showing presence of more than one binding sites for these molecules in enzyme protein and allosteric nature of the filarial enzyme. The product inhibition studies gave us the only compatible mechanism of random addition process with a probable orientation of substrates and products on the enzyme surface.

Rubber fatigue life under multiaxial loading: Numerical and experimental investigations

Numerical and experimental aspects of rubber fatigue crack initiation are investigated in this study. A parameter based on the strain energy density (SED) and predicting the onset of primary crack and its probable orientation was identified for such materials according to the investigations of Mars and Fatemi [1]. In a last work, we have analytically developed this criterion for simple tension (UT), biaxial tension (BT) and simple shear (SS) loadings in the framework of finite strains. The results denote the possibility to predict the orientation plane in which the primary crack would be expected to occur in a material. Then, it was implemented in a finite elements (FE) program. FE and analytical results for the usual strain states were compared and perfect agreement was highlighted. In this study, the load history dependence of the criterion is also pointed out and discussed. Finally, to evaluate life time up to crack nucleation, we have achieved a set of experimental fatigue tests using uniaxial tension (UT) and pure shear (PS) test specimens containing a hole in order to localise the crack initiation. We have also exploited a literature database issued from uniaxial and torsion fatigue tests. The obtained results prove the efficiency of the criterion to describe the fatigue life of rubbers under multiaxial loading.

The role of soil gas radon survey in exploring unknown subsurface faults at Afamia B dam, Syria

The purpose of this work is to determine a possible connection between anomalous radon values and some expected subsurface geological faults at Afamia B dam which is currently suffering a serious problem of large leakage through its bedrocks. A total of 82 soil gas radon sampling points were measured, using direct active method, over an area of 300 × 300 m which almost covers the entire surface of the reservoir basin. The results revealed a reasonable correlation between the geometric pattern of radon anomalies and the probable orientation of some underlying tectonic lineaments. Abnormal radon values, with peak signals of about 2–5 times higher than the background level, led to the detection of two probable fractured zones, denoted as F 1 and F 2. The data analysis suggests that the leakage of water from Afamia B dam almost runs vertically downwards along N60E trending fault zone F 2. Such a fault is very likely extending down within the Neogene formation to reach the permeable karstic carbonate rocks of Cretaceous at depth, forming large conduits through which the water of the reservoir is possibly drained off. This suggestion was in agreement with the general direction of the groundwater flow in the study area which indicates clearly that the supposed fractured zone F 2 may represent a catchment area for groundwater, and thereby it may constitute the most important structural element concerning the leakage problem of Afamia B reservoir.

A Simple Model for the Secular Light Curve of Comet C/1996 B2 Hyakutake

AbstractThe secular light curves of comets (Ferrín, 2005) give a large amount of physical information on the cometary nucleus. We have developed a model that allows the prediction of a secular light curve, from which we derive parameters like the orientation of the rotational axis (I, φ) and optical thickness of the cometary coma. The model is based on the paper published by (Cowan & A'Hearn, 1979). To do the calculation we found a correlation between the water production rate and the reduced magnitude. We obtain probable orientations of the nucleus pole for several combinations of parameters for comet C/1996 B2 Hyakutake.

Simulation and experimental study of intercalation of urea in kaolinite

Experimental measurements and molecular simulations were used to describe the characteristics of the kaolinite/urea intercalation compound. The intercalation compound was synthesized by a mechanochemical method and examined by X-ray diffraction and thermogravimetry. Additionally, a series of NpT (constant particle number–pressure–temperature) simulations was performed to identify thermodynamically stable basal spacings. From the simulations the most probable molecular orientations were determined for single and double layered arrangements of urea molecules that develop between the layers of kaolinite.

Determining the Orientation of Protegrin-1 in DLPC Bilayers Using an Implicit Solvent-Membrane Model

Continuum models that describe the effects of solvent and biological membrane molecules on the structure and behavior of antimicrobial peptides, holds a promise to improve our understanding of the mechanisms of antimicrobial action of these peptides. In such methods, a lipid bilayer model membrane is implicitly represented by multiple layers of relatively low dielectric constant embedded in a high dielectric aqueous solvent, while an antimicrobial peptide is accounted for by a dielectric cavity with fixed partial charge at the center of each one of its atoms. In the present work, we investigate the ability of continuum approaches to predict the most probable orientation of the β-hairpin antimicrobial peptide Protegrin-1 (PG-1) in DLPC lipid bilayers by calculating the difference in the transfer free energy from an aqueous environment to a membrane-water environment for multiple orientations. The transfer free energy is computed as a sum of two terms; polar/electrostatic and non-polar. They both include energetic and entropic contributions to the free energy. We numerically solve the Poisson-Boltzmann equation to calculate the electrostatic contribution to the transfer free energy, while the non-polar contribution to the free energy is approximated using a linear solvent accessible surface area relationships. The most probable orientation of PG-1 is that with the lowest relative transfer free energy. Our simulation results indicate that PG-1 assumes an oblique orientation in DLPC lipid bilayers. The predicted most favorable orientation was with a tilt angle of 19°, which is in qualitative agreement with the experimentally observed orientations derived from solid-state NMR data.

Expectation-Maximization Algorithm with Local Adaptivity

We develop an expectation-maximization algorithm with local adaptivity for image segmentation and classification. The key idea of our approach is to combine global statistics extracted from the Gaussian mixture model or other proper statistical models with local statistics and geometrical information, such as local probability distribution, orientation, and anisotropy. The combined information is used to design an adaptive local classification strategy that improves the robustness of the algorithm and also keeps fine features in the image. The proposed methodology is flexible and can be easily generalized to deal with other inferred information/quantities and statistical methods/models.

Prevalence of Trichophyton rubrum in Tehran, Isolated from Different Levels of Society and Study of Its Probable Organ Orientation

Candidiasis and systemic candidiasis are on the rise in recent years, especially in immunologically challenged persons. Morphology switching in Candida albicans, the most virulent human fungal pathogen, has been identified as one important factor of virulence. Nevertheless, the exact mechanism of this phenomenon has not been fully understood. This has prompted intensive research into the genetic aspects of Candida albicans pathogenicity, albeit the elusive gene(s) causing morphology switching has not been uncovered. In our study, an uncharacterized gene fragment of interest was previously found via differential display reverse transcription-PCR. A1—1 was identified as upregulated in the Candida albicans hyphal forms at 1, 3 and 6 hours after hyphal induction compared to the yeast form. The differential expression of A1—1 in yeast-hyphae switching was then studied in further detail. Candida albicans yeast forms were grown at 25 ◦C in Winge medium. Half of this culture was incubated in hyphal-induction conditions in RPMI-1640 added with penicillin-streptomycin and fetal bovine serum at 37 ◦C with 5% CO2. RNA from the yeast form and hyphal forms at 1, 3, 6, 12 and 24 hour time-points were extracted. All RNA were reverse transcribed into cDNA. A1—1 sequence-specific primers were designed, with betaactin as the housekeeping gene. The Pfaffl mathematical method of relative quantitative real-time PCR using SYBR Green was used to validate the differential expression. A1—1 was found to be upregulated in the hyphal forms of Candida albicans. This gene fragment has presented itself as an interesting target for ongoing further studies to elucidate the function of this potentially novel gene in Candida albicans yeast-hyphae morphology switching.

Discovery of Novel Anticancer Compounds Based on a Quinoxalinehydrazine Pharmacophore

Quinoxalinehydrazines represent a novel class of compounds with excellent potency in a panel of cancer cell lines. A prototype compound, SC144, showed significant in vivo efficacy in mice xenograft models of human breast cancer cells. The subsequent structure-activity relationship study resulted in the discovery of SC161 with better potency in cancer cell lines. Further exploring the possible conformational space by a 10 ns molecular dynamics simulation as presented herein, resulted in various pharmacophore orientations. The trajectory analysis indicated that in most of the simulation time, the molecule stays favorably in a compact planarlike orientation. We therefore built a pharmacophore model based on the cluster containing the highest number of frames to represent the most probable orientation. The model was used to screen a subset of our small molecule database containing 350,000 compounds. We selected 35 compounds for the initial cytotoxicity screen. Seventeen compounds belonging to oxadiazolopyrazine and quinoline class displayed cytotoxicity in various cancer cell lines. Five of them, compounds 2, 6, 15, 16, and 19, all bearing an oxadiazolopyrazine scaffold, showed IC(50) values <3 muM in certain tumor cell lines. The most potent compound, 2, showed IC(50) values <2 muM in HCT116 p53(+/+), HCT116 p53(-/-), and HEY cells, and 8 muM in NIH3T3 cells. This study shows that conformational sampling of a lead small molecule followed by representative pharmacophore model development is an efficient approach for the rational design of novel anticancer agents with similar or better potency than the original lead but with different physicochemical properties.

Influence of the Interstellar Magnetic Field and Neutrals on the Shape of the Outer Heliosphere

Formed as a result of the solar wind (SW) interaction with the circum-heliospheric interstellar medium (CHISM), the outer heliosphere is generically three-dimensional because of the SW asphericity and the action of the interstellar and interplanetary magnetic fields (ISMF and IMF). In this paper we show that charge exchange between neutral and charged components of the SW–CHISM plasmas plays a dominant role not only in determining the geometrical size of the heliosphere, but also in the modulation of magnetic-field-induced asymmetries. More specifically, charge exchange between SW and CHISM protons and primary neutrals of interstellar origin always acts to decrease the asymmetry of the termination shock and the heliopause, which can otherwise be very large. This is particularly pronounced because the ionization ratio of the CHISM plasma is rather low. To investigate the deflection of the CHISM neutral hydrogen flow in the inner heliosphere from its original orientation in the unperturbed CHISM, we create two-dimensional neutral H velocity distributions in the inner heliosphere within a 45-degree circular conical surface with the apex at the Sun and the axis parallel to the interstellar flow vector. It is shown that the distribution of deflections is very anisotropic, that is, the most probable orientation of the H-atom velocity differs from its average direction. We show that the average deflection of the H-atom flow, for reasonable ISMF strengths, occurs mostly in the plane formed by the ISMF and CHISM velocity vectors at infinity. The possibility that the ISMF orientation may influence the 2–3 kHz radio emission, which is believed to originate in the outer heliosheath, is discussed.

Study of the Interaction between Progesterone and β-Cyclodextrin by Electrochemical Techniques and Steered Molecular Dynamics

The interaction of progesterone with beta-cyclodextrin (beta-CD) was studied by differential pulse polarography. The aim of the present work was to study the effect of beta-CD on the electrochemical behavior of progesterone in aqueous solution and also to analyze the molecular interactions involved in formation of the inclusion complex. The complex with stoichiometry of 1:1 was thermodynamically characterized. In addition, steered molecular dynamics (SMD) was used to investigate the energetic properties of formation of the inclusion complex along four different pathways (reaction coordinates), considering two possible orientations. From multiple trajectories along these pathways, the potentials of mean force for formation of the beta-CD progesterone inclusion complex were calculated. The energy analysis was in good agreement with the experimental results. In the beta-CD progesterone inclusion complex, a large portion of the steroid skeleton is included in the beta-CD cavity. The lowest energy was found when the D-ring of the guest molecule is located near the secondary hydroxyls of the beta-CD cavity. In the most probable orientation, one intermolecular hydrogen bond is formed between the O of the C-20 keto group of the progesterone and a secondary hydroxyl of the beta-CD.

Are optically active three-dimensional oxalate-based ferromagnets good candidates for theobservation of x-ray magnetochiral dichroism? A neutron diffraction study

Neutron diffraction studies have been performed on[Ru(bpy)2(ppy)][MnCr(ox)](bpy = 2, 2′bipyridine;ppyH = 2-phenylpyridine;ox = oxalate), a3D oxalate-based compound in one of its optically active forms. The diffraction pattern matches withthe P 213 space group found by x-ray diffraction. The magnetic structure has been studied in themagnetically ordered phase of the compound, e.g. below 5.5 K. The compound ordersferromagnetically. Owing to the most probable orientation of the spins, the magnetic space group isP 2121′21′. The Shubnikovgroup is then 22′2′. Such a magnetic point group is compatible with the observation of x-ray magnetochiraldichroism, the occurrence of a ferromagnetic ordering being an important factor toenhanced the forecast effect.

Humic acids as molecular assemblers in the surface-enhanced Raman scattering detection of polycyclic aromatic hydrocarbons

A humic acid (HA) extracted from lignite was successfully used in surface-enhanced Raman scattering SERS experiments as molecular occlusion assembler deposited onto a Ag colloidal surface to detect the polycyclic aromatic hydrocarbons PAHs chrysene and pyrene. Thus, this is the first time that HA compounds are employed in the design of metal nanoparticles-based sensors for pollutants detection. Chrysene (Chr) and pyrene (Pyr) were detected at low concentration. A charge transfer between HA and the analyte characterizes their interaction. The interaction resulted to be more significant in the case of the pyrene molecule. Extended Hückel calculations based on a molecular model for the interacting PAHs/HA/Ag system support the experimental conclusions. The PAHs–HA distance is about 3.5 Å and the most probable orientation for both analytes is plane parallel to the aromatic fragments of HA. An energy transfer, from the silver surface to HA and from the analyte to HA, is concluded.

Microdomains in mixed monolayers of oleanolic and stearic acids: thermodynamic study and BAM observation at the air–water interface and AFM and FTIR analysis of LB monolayers

Monolayers of oleanolic acid (OLA) mixed with stearic acid (SA) were studied at the air–water interface. The surface pressure–area ( π– A) isotherms, measured over the whole composition range, and BAM observations were used to investigate the phase behaviour and self-organization of these components in a two-dimensional structure. Pure OLA forms a very compressible monolayer, and BAM observation revealed the coexistence of large and irregular solid domains of different thickness dispersed in a gas matrix, compatible with the two most probable orientations of the OLA molecule at the interface. Mixtures of OLA/SA form condensed monolayers from low surface pressures and the thermodynamic analysis indicates that OLA molecules, in the presence of the long-chain SA, orient with the major axis almost perpendicular to the interface. Langmuir–Blodgett (LB) monolayers of pure SA and mixtures were further characterized by atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR). AFM images of LB mixed monolayers evidenced microphase separation, not observable by BAM. The SA rich domains are 4–6 Å thicker than those rich in OLA. The FTIR spectra of mixed LB films on CaF 2 substrates showed that OLA does not perturb the all- trans conformation of the SA long alkyl chains, up to a mole fraction of 0.4. The carbonyl-stretching band of OLA suggests that the carboxylic groups of neighbour OLA molecules are involved in hydrogen bonds, forming dimers, as in pure solid phase OLA. These interactions seem to prevail over the OLA–water hydrogen bonds.

Atomic Decoration for Improving the Efficiency of Field Electron Emission of Carbon Nanotubes

The field electron emission from the single-walled carbon nanotubes with their open ends terminated by -BH, -NH, and -O has been simulated. We find that -BH and -NH suppress the apex−vacuum barrier significantly and lead to higher emission current in contrast to the -O-terminated structure. The calculated binding energy implies that the carbon nanotubes terminated with -BH and -NH are more stable than those saturated by oxygen atoms or by hydrogen atoms. The simulation shows that the most probable orientation of the emission beam has correlation to the atomic structure of the apex and is field-dependent.