Kinetic and molecular orbital studies on the rate of oxidation of monosubstituted phenols and anilines by lactoperoxidase compound II in comparison with the case of horseradish peroxidase

The second-order rate constant (k4) for the oxidation of monosubstituted phenols and anilines by lactoperoxidase compound II was examined by Chance's method [B. Chance, Arch. Biochem. Biophys. 71 (1957), 130–136]. When the electronic states of these substrates were calculated by an ab initio molecular orbital method, it was found that the log k4 value correlates well with the highest occupied molecular orbital (HOMO) energy level but not with the net charge or frontier electron density. These results are essentially similar to those reported previously in the case of horseradish peroxidase [J. Sakurada, R. Sekiguchi, K. Sato, and T. Hosoya, Biochemistry 29 (1990), 4093–4098], showing some dissimilar features which are considered to reflect the structural difference between the two enzymes.Abbreviations HOMO highest occupied molecular orbital - HRP horseradish peroxidase - LPO lactoperoxidase (EC 1.11.1.7) - LUMO lowest unoccupied molecular orbital     

Anisotropic intersubunit and inter-ring interactions revealed in the native bullet-shaped chaperonin complex from Thermus thermophilus

Background

The recent morphological studies on chaperonins have revealed that nearly equivalent amount of symmetric GroEL–(GroES)₂ (football-shaped) and asymmetric GroEL–GroES (bullet-shaped) complexes coexist during the chaperonin reaction cycle, which prompted us to reexamine the equatorial split observed for chaperonin from Thermus thermophilus by implementing semi-empirical molecular orbital (MO) calculations, since it is now believed that the symmetric formation is a precursor to the equatorial split.

Methods

Semi-empirical MO calculations were employed to investigate the intersubunit interactions within the bullet-shaped T. thermophilus chaperonin capturing the substrate of folding intermediates. Interaction energies between each cis-GroEL subunit and closely related remaining subunits in cis-GroEL ring, or in trans-GroEL ring across the equatorial plane, and further, interaction energies between each GroES subunit and adjacent subunits in the same GroES ring and in cis-GroEL ring were simulated.

Results

Anisotropic intensities and energy distribution of the subunits were revealed by the calculations, which are consistent with two conformations of the subunits forming cis-GroEL ring as revealed by X-ray crystal structure, and with an anisotropic critical binding site on cis-GroEL ring for chaperonin functioning.

Conclusions

This is the first application of semi-empirical MO calculations to the macromolecular complex of the native bullet-shaped chaperonin (GroEL–GroES–ADP homolog) from T. thermophilus.

General significance

The results also appear to support the occurrence of the equatorial split for T. thermophilus chaperonin observed via electron microscopy, but has not yet been fully observed for Escherichia coli GroEL–GroES system.     

Molecular structure,spectroscopic (FT-IR,FT-Raman,UV–vis), NBO,thermochemistry analysis of bis(thiourea)zinc(II) chloride crystals

The experimental and theoretical studies on the molecular structure and vibrational spectra of bis(thiourea)zinc(II) chloride (BTZC) crystals were investigated. The Fourier transform infrared, Fourier transform Raman and UV–vis spectra of BTZC were recorded. The molecular geometry and vibrational frequencies of BTZC in the ground state were calculated by using B3LYP with LANL2DZ as basis set. Comparison of the observed structural parameters of BTZC with single-crystal X-ray studies yields a good agreement. Vibrational analysis of the simultaneous IR and Raman activation of the Zn–Cl stretching mode in the molecule provides the evidence for the charge transfer interaction taking place within the molecule. The energy and oscillator strength are calculated by time-dependent density functional theory. The simulated spectra satisfactorily coincide with the experimental spectra.     

Ab initio fragment molecular orbital calculations on the specific interactions between human,mouse and rat PPARα and GW409544

To elucidate the specific interactions between the peroxisome proliferator-activated receptor (PPARα) and ligand GW409544 (GW), we obtained the solvated structures of the PPARα+GW complexes for human, mouse and rat by classical molecular mechanics calculations, and investigated their electronic properties by ab initio fragment molecular orbital calculations. The results indicate that the positively charged amino acids (Lys and Arg) of PPARα make a major contribution to the binding between PPARα and GW. In addition, it was clarified that Ser280 and Tyr314 of human and rat PPARα have a large attractive interaction with GW, while Ser280, Tyr314 and His440 of mouse PPARα have large interaction. These results on the difference in specific interactions between human and mouse/rat PPARα will be useful for predicting the effects of new chemicals on the human body based on the biomedical studies for the experimental animals such as mouse and rat.     

Quantum chemical study of the structure and properties of citrinin

Detailed structures and electronic properties of three tautomeric forms of the toxin citrinin were investigated using several quantum calculation methods. Energetic preference of the predominant p- and o-quinone methide tautomeric forms is dependent on the method of calculation. A previously unstudied carboxylic acid enol tautomer was calculated to be surprisingly stable in vacuo, being within 2.5 kcal mol^? 1 at the B3LYP/6-311++G(2d,2p) level of theory. Despite differences in bond nature and connectivity of tautomers, the natural bond orbital analysis revealed that tautomeric forms share similar natural charges and natural electron configurations. Calculated bond lengths corresponded with experimentally observed values and assignments for the calculated infrared vibrational frequencies are reported.     

Influence of HOCl…O3 and HOCl…HOCl interactions on the stability of O3(HOCl)2 complexes: a theoretical study

We have analysed the role of HOCl…O₃ and HOCl…HOCl interactions on the stability of four estimated O₃(HOCl)₂ complexes by means of ab initio molecular orbital calculations. It is predicted that the O₃(HOCl) + HOCl reaction is more energetically favourable than (HOCl)₂ + O₃ one. In all complexes, HOCl…HOCl interaction is stronger than HOCl…O₃ one. The results show that the HOCl…O₃ interaction strengthens the HOCl…HOCl one. On the other hand, O…H interaction in HOCl…O₃ moiety is strengthened when it interacts with HOCl. Quantum theory of atoms in molecules predicts that the weak interactions in O₃(HOCl)₂ complexes have electrostatic characteristic. In all complexes, the charge transfer from O₃ to (HOCl)₂ is expected from natural bond orbital analysis.     

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC₅₀ = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R² of 0.81.     

Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate

A small library of antiplasmodial methoxy-thiazinoquinones, rationally designed on the model of the previously identified hit 1, has been prepared by a simple and inexpensive procedure. The synthetic derivatives have been subjected to in vitro pharmacological screening, including antiplasmodial and toxicity assays. These studies afforded a new lead candidate, compound 9, endowed with higher antiplasmodial potency compared to 1, a good selectivity index when tested against a panel of mammalian cells, no toxicity against RBCs, a synergistic antiplasmodial action in combination with dihydroartemisinin, and a promising inhibitory activity on stage V gametocyte growth. Computational studies provided useful insights into the structural requirements needed for the antiplasmodial activity of thiazinoquinone compounds and on their putative mechanism of action.     

The crystal structure of 1,2,3,4,6-penta-O-benzoyl-alpha-D-mannopyranose: observation of C-H...pi interaction as a surrogate to O-H...O interaction of a free sugar

The crystal structure of the title compound was determined by X-ray crystallography. The compound crystallized in the orthorhombic space group P2(1)2(1)2(1) with four molecules in the unit cell with a=9.170(2), b=9.873 (2), c=38.831(8) A. The structure was refined to a R index of 0.041 for 7907 independent reflections. The mannopyranose unit adopts a distorted 4C1 conformation. The structure depicts unique network of C-H...pi interactions, very closely resembling the pattern of O-H...O interactions in free sugars. This intriguing and rare observation points to a notion that the supramolecular organization pertaining to a sugar is in-built in the pyranose ring itself.     

Mapping bone cell distributions to assess ontogenetic origin of primate midfacial form

Midfacial reduction in primates has been explained as a byproduct of other growth patterns, especially the convergent orbits. This is at once an evolutionary and developmental explanation for relatively short snouts in most modern primates. Here, we use histological sections of perinatal nonhuman primates (tamarin, tarsier, loris) to investigate how orbital morphology emerges during ontogeny in selected primates compared to another euarchontan (Tupaia glis). We annotated serial histological sections for location of osteoclasts or osteoblasts, and used these to create three‐dimensional “modeling maps” showing perinatal growth patterns of the facial skeleton. In addition, in one specimen we transferred annotations from histological sections to CT slices, to create a rotatable 3D volume that shows orbital modeling. Our findings suggest that growth in the competing orbital and neurocranial functional matrices differs among species, influencing modeling patterns. Distinctions among species are observed in the frontal bone, at a shared interface between the endocranial fossa and the orbit. The medial orbital wall is extensively resorptive in primates, whereas the medial orbit is generally depositional in Tupaia. As hypothesized, the orbital soft tissues encroach on available interorbital space. However, eye size cannot, by itself, explain the extent of reduction of the olfactory recess. In Loris, the posterior portion of medial orbit differed from the other primates. It showed evidence of outward drift where the olfactory bulb increased in cross‐sectional area. We suggest the olfactory bulbs are significant to orbit position in strepsirrhines, influencing an expanded interorbital breadth at early stages of development. Am J Phys Anthropol 154:424–435, 2014. © 2014 Wiley Periodicals, Inc.