Modeling flexible pharmacophores with distance geometry, scoring, and bound stretching

The study of pharmacophores, i.e., of common features between different ligands, is important for the quantitative identification of "compatible" enzymes and binding species. A pharmacophore-based technique is developed that combines multiple conformations with a distance geometry method to create flexible pharmacophore representations. It uses a set of low-energy conformations combined with a new process we call bound stretching to create sets of distance bounds, which contain all or most of the low-energy conformations. The bounds can be obtained using the exact distances between pairs of atoms from the different low-energy conformations. To avoid missing conformations, we can take advantage of the triangle distance inequality between sets of three points to logically expand a set of upper and lower distance bounds (bound stretching). The flexible pharmacophore can be found using a 3-D maximal common subgraph method, which uses the overlap of distance bounds to determine the overlapping structure. A scoring routine is implemented to select the substructures with the largest overlap because there will typically be many overlaps with the maximum number of overlapping bounds. A case study is presented in which 3-D flexible pharmacophores are generated and used to eliminate potential binding species identified by a 2-D pharmacophore method. A second case study creates flexible pharmacophores from a set of thrombin ligands. These are used to compare the new method with existing pharmacophore identification software.     

Regioselectivity of aliphatic versus aromatic hydroxylation by a nonheme iron(II)-superoxo complex

Many enzymes in nature utilize molecular oxygen on an iron center for the catalysis of substrate hydroxylation. In recent years, great progress has been made in understanding the function and properties of iron(IV)-oxo complexes; however, little is known about the reactivity of iron(II)-superoxo intermediates in substrate activation. It has been proposed recently that iron(II)-superoxo intermediates take part as hydrogen abstraction species in the catalytic cycles of nonheme iron enzymes. To gain insight into oxygen atom transfer reactions by the nonheme iron(II)-superoxo species, we performed a density functional theory study on the aliphatic and aromatic hydroxylation reactions using a biomimetic model complex. The calculations show that nonheme iron(II)-superoxo complexes can be considered as effective oxidants in hydrogen atom abstraction reactions, for which we find a low barrier of 14.7 kcal mol(-1) on the sextet spin state surface. On the other hand, electrophilic reactions, such as aromatic hydroxylation, encounter much higher (>20 kcal mol(-1)) barrier heights and therefore are unlikely to proceed. A thermodynamic analysis puts our barrier heights into a larger context of previous studies using nonheme iron(IV)-oxo oxidants and predicts the activity of enzymatic iron(II)-superoxo intermediates.     

Evaluation of MRI issues at 3-Tesla for a hospital identification (ID) wristband

Background and Purpose

A recent report suggested that a serious burn injury was due to the presence of the identification (ID) wristband. As such, in lieu of removing or padding hospital ID wristbands in all patients prior to magnetic resonance imaging (MRI), testing may be performed to characterize risks for ID wristbands. Therefore, the purpose of this investigation was to evaluate the magnetic field interactions, heating and artifacts at 3 T for a hospital ID wristband.

Materials and Methods

Standardized test methods were used to evaluate magnetic field interactions, MRI-related heating, and artifacts at 3 T for a hospital ID wristband.

Results

There were no magnetic field interactions. MRI-related heating evaluated at a relatively high, MR system-reported, whole body-averaged specific absorption rate (2.9 W/kg) did not increase above the background level. The artifacts related to the ink used for printing were “small” for one toner and “large” for the other in relation to the dimensions of the printing.

Conclusions

Based on the tests performed, this particular hospital ID wristband is considered MR safe and will not pose a hazard to a patient undergoing an MRI examination. Importantly, it is not necessary to remove this item for a patient referred for MRI.     

Octave-spanning supercontinuum generation of vortices in an As2S3 ring photonic crystal fiber

We propose As(2)S(3) ring photonic crystal fiber (PCF) for supercontinuum generation of optical vortex modes. Due to the large material index contrast between As(2)S(3) and air holes in the designed ring PCF, there is a two-orders-of-magnitude improvement of the difference between the effective refractive indices of different vortex modes compared with regular ring fiber. The design freedom of PCFs enables a low dispersion (<60 ps/nm/km variation in total) over a 522 nm optical bandwidth. Moreover, the vortex mode has a large nonlinear coefficient of 11.7/W/m at 1550 nm with a small confinement loss of <0.03 dB/m up to 2000 nm. An octave-spanning supercontinuum spectrum of the vortex mode is generated from 1196 to 2418 nm at -20 dB by launching a 120 fs pulse with a 60 W peak power at 1710 nm into a 1 cm long As(2)S(3) ring PCF.     

Localized growth and in situ integration of nanowires for device applications

Simultaneous localized growth and device integration of inorganic nanostructures on heated micromembranes is demonstrated for single crystalline germanium and tin oxide nanowires. Fully operating CO gas sensors prove the potential of the presented approach. With this simple CMOS compatible technique, issues of assembly, transfer and contact formation are addressed.     

Nonheme iron-oxo and -superoxo reactivities: O2 binding and spin inversion probability matter

DFT calculated barriers for C-H activation of 1,4-cyclohexadiene by nonheme iron(IV)-oxo and iron(III)-superoxo species show that the experimental trends can be explained if the spin inversion probability of the TMC iron(IV)-oxo is assumed to be poor. Also, the TMC iron(III)-superoxo reaction proceeds with an endothermic O(2)-binding energy followed by an intrinsically reactive quintet state.     

Axial and equatorial ligand effects on biomimetic cysteine dioxygenase model complexes

Density functional theory (DFT) calculations are presented on biomimetic model complexes of cysteine dioxygenase and focus on the effect of axial and equatorial ligand placement. Recent studies by one of us [Y. M. Badiei, M. A. Siegler and D. P. Goldberg, J. Am. Chem. Soc. 2011, 133, 1274] gave evidence of a nonheme iron biomimetic model of cysteine dioxygenase using an i-propyl-bis(imino)pyridine, equatorial tridentate ligand. Addition of thiophenol, an anion - either chloride or triflate - and molecular oxygen, led to several possible stereoisomers of this cysteine dioxygenase biomimetic complex. Moreover, large differences in reactivity using chloride as compared to triflate as the binding anion were observed. Here we present a series of DFT calculations on the origin of these reactivity differences and show that it is caused by the preference of coordination site of anion versus thiophenol binding to the chemical system. Thus, stereochemical interactions of triflate and the bulky iso-propyl substituents of the ligand prevent binding of thiophenol in the trans position using triflate. By contrast, smaller anions, such as chloride, can bind in either cis or trans ligand positions and give isomers with similar stability. Our calculations help to explain the observance of thiophenol dioxygenation by this biomimetic system and gives details of the reactivity differences of ligated chloride versus triflate.     

Single-step fabrication of patterned gold film array by an engineered multi-functional peptide

This study constitutes a demonstration of the biological route to controlled nano-fabrication via modular multi-functional inorganic-binding peptides. Specifically, we use gold- and silica-binding peptide sequences, fused into a single molecule via a structural peptide spacer, to assemble pre-synthesized gold nanoparticles on silica surface, as well as to synthesize nanometallic particles in situ on the peptide-patterned regions. The resulting film-like gold nanoparticle arrays with controlled spatial organization are characterized by various microscopy and spectroscopy techniques. The described bio-enabled, single-step synthetic process offers many advantages over conventional approaches for surface modifications, self-assembly and device fabrication due to the peptides' modularity, inherent biocompatibility, material specificity and catalytic activity in aqueous environments. Our results showcase the potential of artificially-derived peptides to play a key role in simplifying the assembly and synthesis of multi-material nano-systems in environmentally benign processes.     

‘Excellent’ primary mathematics teachers’ espoused and enacted values of effective lessons

This paper reports a study that explored the characteristics of mathematics lessons that were espoused as effective by six ??excellent?? mathematics teachers and how they enacted their values in their classroom practice. In this study, we define espoused values as values that we want other people to believe we hold, and enacted values as values that we actually practice. Qualitative data were collected through video-recorded lesson observations (3 lessons for each teacher) and in-depth interviews with teachers after each observation. At the end of the project, stimulated-recall focus group interviews were used to allow teachers to define the meaning of an effective mathematics lesson as well as to recall and reflect on a 10-min edited video clip of one of their teaching lessons. The findings showed that these teachers shared five common characteristics of effective mathematics lessons: achieving teaching objectives; pupils?? cognitive development; affective achievement of pupils; focus on low-attaining pupils; and active participation of pupils in mathematics activities. These values were espoused explicitly as well as enacted in the lessons observed.