Stem Region of tRNA Genes Favors Transition Substitution Towards Keto Bases in Bacteria.

Transversion and transition mutations have variable effects on the stability of RNA secondary structure considering that the former destabilizes the double helix geometry to a greater extent by introducing purine:purine (R:R) or pyrimidine:pyrimidine (Y:Y) base pairs. Therefore, transversion frequency is likely to be lower than that of transition in the secondary structure regions of RNA genes. Here, we performed an analysis of transition and transversion frequencies in tRNA genes defined well with secondary structure and compared with the intergenic regions in five bacterial species namely Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Staphylococcus aureus and Streptococcus pneumoniae using a large genome sequence data set. In general, the transversion frequency was observed to be lower than that of transition in both tRNA genes and intergenic regions. The transition to transversion ratio was observed to be greater in tRNA genes than that in the intergenic regions in all the five bacteria that we studied. Interestingly, the intraspecies base substitution analysis in tRNA genes revealed that non-compensatory substitutions were more frequent than compensatory substitutions in the stem region. Further, transition to transversion ratio in the loop region was observed to be significantly lesser than that among the non-compensatory substitutions in the stem region. This indicated that the transversion is more deleterious than transition in the stem regions. In addition, substitutions from amino bases (A/C) to keto bases (G/T) were also observed to be more than the reverse substitutions in the stem region. Substitution from amino bases to keto bases are likely to facilitate the stable G:U pairing unlike the reverse substitution that facilitates the unstable A:C pairing in the stem region of tRNA. This work provides additional support that the secondary structure of tRNA molecule is what drives the different substitutions in its gene sequence.

First Report of Plant-Derived ß-Sitosterol with Antithrombotic, in Vivo Anticoagulant, and Thrombus-Preventing Activities in a Mouse Model.

Inhibitors of thrombin, a key enzyme in the blood coagulation cascade, are of great interest because of their selective specificity and effectiveness in anticoagulation therapy against cardiovascular disorders. The natural soybean phytosterol, ß-sitosterol (BSS) demonstrated anticoagulant activity by dose-dependent inhibition of thrombin in an uncompetitive manner with a Ki value of 0.267 µM as well as by partial inhibition of thrombin-catalyzed platelet aggregation with a half-maximal inhibitory concentration (IC50) value of 10.45 ± 2.88 µM against platelet-rich plasma and 9.2 ± 1.2 µM against washed platelets. An in silico study indicated binding of BSS to thrombin, which was experimentally verified by spectrofluorometric and isothermal calorimetric analyses. Under in vitro conditions, BSS demonstrated thrombolytic activity by activating plasminogen, albeit it is devoid of protease (fibrinogenolytic) activity. BSS was noncytotoxic to mammalian cells, nonhemolytic, demonstrated its in vivo anticoagulant activity when administered orally, and inhibited k-carrageen-induced thrombus formation in the tails of mice. Our results suggest that dietary supplementation of BSS may help to prevent thrombosis-associated cardiovascular disorders.

Reaction of a copper(II)-nitrosyl complex with hydrogen peroxide: phenol ring nitration through a putative peroxynitrite intermediate.

Copper(II) complex, 1, with the histidine-derived ligand L (L = methyl 2-(2-hydroxybenzylamino)-3-(1H-imidazol-5-yl)propanoate) has been synthesized and characterized. Single-crystal structure determination reveals a diphenolato-bridged dicopper(II) core in 1. Addition of (•)NO to an acetonitrile solution of 1 affords the corresponding mononuclear copper(II)-nitrosyl complex, 2. In the presence of H2O2, 2 results in formation of the corresponding copper(I)-peroxynitrite. Formation of peroxynitrite ((-)OONO) intermediate is evident from its characteristic phenol ring nitration reaction which resembles the tyrosine nitration in biological systems. Further, isolation of nitrate (NO3(-)) as the decomposition product from 2 at room temperature also supports the involvement of (-)OONO intermediate.

Enantioselective Henry reaction catalyzed by "ship in a bottle" complexes.

Two chiral Schiff-base complexes of copper(II) have been successfully encapsulated inside the cavity of zeolite-NaY via a "ship in a bottle" synthesis method. The presence of the two complexes inside the cages of zeolite-Y has been confirmed based on various spectrochemical and physicochemical techniques, viz. FTIR, UV-vis/DRS, ESR, XPS, CV, EDX, SEM, and TGA. Zeolite-encapsulated chiral copper(II) Schiff-base complexes are found to give a high-enantioselective (84% ee, R conformation) nitro-aldol product at -20 °C. The encapsulated copper complexes are found to show higher catalytic efficiency than their homogeneous counterparts under identical conditions. Density functional theory (DFT) calculation has been implemented to understand the effect of the zeolite matrix on structural, electronic, and reactivity properties of the synthesized complexes. Theoretical calculation predicts that upon encapsulation into the zeolite matrix the Cu center becomes more susceptible to nucleophilic attack, favoring a nitro-aldol reaction. A plausible mechanism is suggested based on the experimental and theoretical results. The structures of reaction intermediates and transition state(s) involved in the catalytic cycle are derived using DFT.

Ab initio study on the noncovalent adsorption of camptothecin anticancer drug onto graphene, defect modified graphene and graphene oxide.

The application of graphene and related nanomaterials like boron nitride (BN) nanosheets, BN-graphene hybrid nanomaterials, and graphene oxide (GO) for adsorption of anticancer chemotherapeutic camptothecin (CPT) along with the effect on electronic properties prior to functionalization and after functionalization has been reported using density functional theory (DFT) calculations. The inclusion of dispersion correction to DFT is instrumental in accounting for van der Waals π-π stacking between CPT and the nanomaterial. The adsorption of CPT exhibits significant strain within the nanosheets and noncovalent adsorption of CPT is thermodynamically favoured onto the nanosheets. In case of GO, surface incorporation of functional groups result in significant crumpling along the basal plane and the interaction is basically mediated by H-bonding rather than π-π stacking. Docking studies predict the plausible binding of CPT, CPT functionalized graphene and GO with topoisomerase I (top 1) signifying that CPT interacts through π stacking with AT and GC base pairs of DNA and in presence of nano support, DNA bases preferentially gets bound to the basal plane of graphene and GO rather than the edges. At a theoretical level of understanding, our studies point out the noncovalent interaction of CPT with graphene based nanomaterials and GO for loading and delivery of anticancer chemotherapeutic along with active binding to Top1 protein.

Density functional and molecular docking studies towards investigating the role of single-wall carbon nanotubes as nanocarrier for loading and delivery of pyrazinamide antitubercular drug onto pncA protein.

The potential biomedical application of carbon nanotubes (CNTs) pertinent to drug delivery is highly manifested considering the remarkable electronic and structural properties exhibited by CNT. To simulate the interaction of nanomaterials with biomolecular systems, we have performed density functional calculations on the interaction of pyrazinamide (PZA) drug with functionalized single-wall CNT (fSWCNT) as a function of nanotube chirality and length using two different approaches of covalent functionalization, followed by docking simulation of fSWCNT with pncA protein. The functionalization of pristine SWCNT facilitates in enhancing the reactivity of the nanotubes and formation of such type of nanotube-drug conjugate is thermodynamically feasible. Docking studies predict the plausible binding mechanism and suggests that PZA loaded fSWCNT facilitates in the target specific binding of PZA within the protein following a lock and key mechanism. Interestingly, no major structural deformation in the protein was observed after binding with CNT and the interaction between ligand and receptor is mainly hydrophobic in nature. We anticipate that these findings may provide new routes towards the drug delivery mechanism by CNTs with long term practical implications in tuberculosis chemotherapy.

Enhanced catalytic activity of zeolite encapsulated Fe(III)-Schiff-base complexes for oxidative coupling of 2-napthol.

Iron(III) Schiff-base complexes of general formula [Fe(L)(2)Cl]·2H(2)O, where L = N,N-bis(salicylidene)ethylenediamine and N,N-disalicylidene-1,2-phenylenediamine have been encapsulated within various alkali exchanged zeolites viz. LiY, NaY, and KY by flexible ligand method. The encapsulated complexes are characterized by EDX, scanning electron microscopy (SEM), powder X-ray diffraction (XRD), FT-IR, UV-vis, diffuse reflectance spectroscopy (DRS), electron spin resonance spectroscopy (ESR) and cyclic voltammetry studies. The diffuse reflectance UV-vis spectra of encapsulated complexes show a dramatic red shift of the charge transfer band with increasing electropositivity of the exchangeable cations. The electrochemical analysis predicts the shifting of the reduction potential toward negative values with increasing size of the alkali exchanged cations. The zeolite encapsulated Schiff-base complexes of iron are found to be catalytically active toward the oxidative coupling of 2-napthol. Metal complexes incorporated in potassium exchanged zeolite-Y are found to be more effective for catalytic conversion of 2-naphthol to binaphthol and induces higher selectivity toward the R-conformation. The catalytic conversion of 2-napthol to BINOL is found to depend on the reduction potential of the catalyst, with a more negative reduction potential being better for the catalytic conversion. Density functional calculation is being carried out on both the neat Fe-Salen and Fe-Salophen complexes and those encapsulated in NaY zeolite to investigate change in structural parameters, energies of the HOMO and LUMO, and global hardness and softness. Fukui functions, as local descriptors, are used to analyze the hard-hard interaction at a particular site of the complexes.

Regioselective Friedel-Crafts Acylation Reaction Using Single Crystalline and Ultrathin Nanosheet Assembly of Scrutinyite-SnO2.

Peculiar physicochemical properties of two-dimensional (2D) nanomaterials have attracted research interest in developing new synthetic technology and exploring their potential applications in the field of catalysis. Moreover, ultrathin metal oxide nanosheets with atomic thickness exhibit abnormal surficial properties because of the unique 2D confinement effect. In this work, we present a facile and general approach for the synthesis of single crystalline and ultrathin 2D nanosheets assembly of scrutinyite-SnO2 through a simple solvothermal method. The structural and compositional characterization using X-ray diffraction (Rietveld refinement analysis), high-resolution transmission electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, and so on reveal that the as-synthesized 2D nanosheets are ultrathin and single crystallized in the scrutinyite-SnO2 phase with high purity. The ultrathin SnO2 nanosheets show predominant growth in the [011] direction on the main surface having a thickness of ca. 1.3 nm. The SnO2 nanosheets are further employed for the regioselective Friedel-Crafts acylation to synthesize aromatic ketones that have potential significance in chemical industry as synthetic intermediates of pharmaceuticals and fine chemicals. A series of aromatic substrates acylated over the SnO2 nanosheets have afforded the corresponding aromatic ketones with up to 92% yield under solvent-free conditions. Comprehensive catalytic investigations display the SnO2 nanosheet assembly as a better catalytic material compared to the heterogeneous metal oxide catalysts used so far in the view of its activity and reusability in solvent-free reaction conditions.

Role of ligand to control the mechanism of nitric oxide reduction of copper(II) complexes and ligand nitrosation.

The nitric oxide reactivity of two copper(II) complexes, 1 and 2 with ligands L(1) and L(2), respectively, [L(1) = 5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane, L(2) = 5,5,7-trimethyl-[1,4]-diazepane] have been studied. The copper(II) center in complex 1 was found to be unreactive toward nitric oxide in pure acetonitrile; however, it displayed reduction in methanol solvent in presence of base. The copper(II) center in 2, in acetonitrile solvent, on exposure to nitric oxide has been found to be reduced to copper(I). The same reduction was observed in methanol, also, in case of complex 2. In case of complex 1, presumably, the attack of nitric oxide on the deprotonated amine is the first step, followed by electron transfer to the copper(II) center to afford the reduction. Alternatively, first NO coordination to the Cu(II) followed by NO(+) migration to the secondary amine is the most probable in case of complex 2. The observation of the transient intermediate in UV-visible and FT-IR spectroscopy prior to reduction in case of complex 2 also supports this possibility. In both cases, the reduction resulted into N-nitrosation; in 1, only mononitrosation was observed whereas complex 2 afforded dinitrosation as major product along with a minor amount of mononitrosation. Thus, it is evident from the present study that the macrocyclic ligands prefer the deprotonation pathway leading to mononitrosation; whereas nonmacrocyclic ones prefer the [Cu(II)-NO] intermediate pathway resulting into nitrosation at all the available sites of the ligand as major product.

Hybrid density functional∕molecular mechanics studies on activated adsorption of oxygen on zeolite supported gold monomer.

Density functional theory calculations on oxygen adsorption over gas phase and faujasite supported Au monomer has been studied using hybrid quantum mechanics∕molecular mechanics method, surface integrated molecular orbital molecular mechanics implemented in GAMESS package. Three different oxidation states of Au (0, +1, +3) and three different adsorption modes viz., top, bridge, and dissociative adsorption of oxygen have been considered in our calculations. Redshift in the ν(O-O) value from that in gas phase O(2) indicates activation of O(2) upon adsorption over faujasite supported gold monomer. The activation of O(2) is an important step in the catalytic oxidation of CO. The presence of adsorbed O(2) increases the interaction of the Au monomer with the faujasite support. In faujasite supported cationic Au monomer, O(2) preferably remains bridge bonded to Au rather than being dissociated.

Design of Potential IKK-ß Inhibitors using Molecular Docking and Molecular Dynamics Techniques for their Anti-cancer Potential.

AIM AND OBJECTIVE: To evaluate a set of seventy phytochemicals for their potential ability to bind the inhibitor of nuclear factor kappaB kinase beta (IKK-ß) which is a prime target for cancer and inflammatory diseases. MATERIALS AND METHODS: Seventy phytochemicals were screened against IKK-ß enzyme using DFT-based molecular docking technique and the top docking hits were carried forward for molecular dynamics (MD) simulation protocols. The ADME-Toxicity analysis was also carried out for the top docking hits. RESULTS: Sesamin, matairesinol and resveratrol were found to be the top docking hits with a total score of -413 kJ/mol, -398.11 kJ/mol and 266.73 kJ/mol, respectively. Glu100 and Gly102 were found to be the most common interacting residues. The result from MD simulation observed a stable trajectory with a binding free energy of -107.62 kJ/mol for matairesinol, -120.37 kJ/mol for sesamin and -40.56 kJ/mol for resveratrol. The ADME-Toxicity prediction observed that these compounds fall within the permissible area of Boiled-Egg and it does not violate any rule for pharmacological criteria, drug-likeness etc. Conclusion: The study interprets that dietary phytochemicals are potent inhibitors of IKK-ß enzyme with favorable binding affinity and less toxic effects. In fact, there is a gradual rise in the use of plant-derived molecules because of its lesser side effects compared to chemotherapy. The study has also provided an insight by which the phytochemicals inhibited the IKK-ß enzyme. The investigation would also provide in understanding the inhibitory mode of certain dietary phytochemicals in treating cancer.

Structural insight into locked nucleic acid based novel antisense modifications: A DFT calculations at monomer and MD simulations at oligomer level.

In the present study, five novel LNA based antisense modifications have been proposed. A conformational search was carried out using TANGO, followed by geometry optimization using MOPAC. Based on their electronic energies the most stable conformation for each modification was identified. Further, DFT based full geometry optimization on the most stable conformations at the gas phase B3LYP/6-31G(d,p) using a Gaussian03 and single point energy calculations on the optimized structures at the solvent phase B3LYP/6-311G(d,p) level of theory were done to derive their quantum chemical descriptors using the Gaussian09. A comparison of global reactivity descriptors confirmed that the LNA based modifications were the most reactive. Base-pair stability was recorded by observing the binding energies and base-pairing conformations of modified GC base pairs at the B3LYP/6-311G(d,p) level of theory. Molecular dynamics simulations have been performed at the oligomer duplex level by incorporating individual modifications on 20-mer RNA-RNA duplexes using AMBER16. Free energy calculations of duplex structures suggested that incorporation of A2 modification into the RNA-RNA duplex increased the duplex binding affinity similar to LNA. Whereas, the A3 modification showed less binding compared to LNA but improved binding compared to MOE. This computational approach using quantum chemical methods may be very useful to propose better modifications than the existing ones before performing the experiments in the area of antisense technology.

Adsorption of CO on oxygen preadsorbed neutral and charged gas phase Pd(4) clusters: A density functional study.

We present the results of a density functional calculation on adsorption of O(2), CO, and their coadsorption at various sites of neutral, cationic, and anionic Pd(4) clusters. For all the clusters, the dissociative adsorption of oxygen sitting on Pd bridge sites is found to be preferable. Both O(2) and CO binding energies are found to be higher for the anionic Pd(4) cluster followed by cationic and neutral cluster. However, binding energies of O(2) or CO in the coadsorption complexes follow the trend: anionic > neutral > cationic.

Quantum chemistry study on absorption spectra, electronic and electrical properties of organic dye on anatase(001).

As the most reactive surface, the stoichiometric O-bridge terminated anatase(001) surface attracted considerable attentions in many application fields. The interfacial electron transfer in dye-sensitized anatase(001) plays a principal role in a variety of photoinduced reactions. In the present work, the UV-vis absorption spectrum of TiO2 bulk and different surface models were calculated by means of tight-binding quantum chemical molecular dynamics program "Colors-excite" for the first time. The thickness dependence on electronic and electrical properties of anatase(001) surface was achieved. The anatase(001) surface with a thickness of 1.0 nm shows excellent electronic and electrical properties. Moreover, the most suitable binding mode (dissociative adsorption) and absorption spectra of perylene with acrylic acid (PAA) on the optimum anatase(001) were investigated. A significant red-shift was observed from the UV-vis absorption spectrum of PAA/anatase(001) system. The red-shift occurring when PAA adsorbed on anatase(001) surface suggests that PAA/anatase(001) may be potential candidate for dye-sensitized solar cell. This study also proposed an effective computational tool "Colors-excite" to study of the electronic excitation properties for both molecular and periodic systems.

Tribochemical reaction dynamics of molybdenum dithiocarbamate on nascent iron surface: a hybrid quantum chemical/classical molecular dynamics study.

Using a hybrid quantum chemical/classical molecular dynamics method, we have studied the tribochemical reaction dynamics of molybdenum dithiocarbamate (MoDTC), a commonly used friction modifier in automobile engine oils. MoDTC molecule adsorbed on rubbing nascent iron surface was situated. We firstly investigated the dynamic behavior of MoDTC molecule on the rubbing Fe(001) surface. During the friction simulation, the elongation of Mo-O bonds was observed, forming the Mo2S4 and thiocarbamic acid molecules. To unveil the detailed mechanism of this bond elongation, the electronic states of the MoDTC molecule and Fe(001) surface were computed, and the catalytic effects of Fe(001) surface to the molecule was found. We also found that extreme friction would influence the complete Mo-O bond dissociation. By using the hybrid quantum chemical/classical molecular dynamics method, we successfully simulated the tribochemical reaction dynamics of MoDTC as a friction modifier and obtained the influences of nascent iron surface and friction on its chemical reaction.

Reaction intermediates of CO oxidation on gas phase Pd4 clusters: a density functional study.

Density functional theory (DFT) studies have revealed the energetically favorable reaction paths for oxidation of CO on Pd(4) cluster. Adsorption of various species such as O(2), 2O, O, CO, CO(2), and coadsorbate combinations, including O(2)+CO, 2O+CO, O+CO, and O+CO(2) on neutral, cationic, and anionic Pd(4) clusters were investigated. The results indicate that Pd(4)(+) and Pd(4) are more effective for catalyzing CO in comparison with Pd(4)(-). It is further observed that dissociated oxygen is a superior oxidant for CO oxidation on Pd(4)(q) (q = 0, 1, -1) than molecular and atomic oxygen.

DFT-based QSAR and QSPR models of several cis-platinum complexes: solvent effect.

Cytotoxic activities of cis-platinum complexes against parental and resistant ovarian cancer cell lines were investigated by quantitative structure-activity relationship (QSAR) analysis using density functional theory (DFT) based descriptors. The calculated parameters were found to increase the predictability of each QSAR model with incorporation of solvent effects indicating its importance in studying biological activity. Given the importance of logarithmic n-octanol/water partition coefficient (log P(o/w)) in drug metabolism and cellular uptake, we modeled the log P(o/w) of 24 platinum complexes with different leaving and carrier ligands by the quantitative structure-property relationship (QSPR) analysis against five different concentrations of MeOH using DFT and molecular mechanics derived descriptors. The log P(o/w) values of an additional set of 20 platinum complexes were also modeled with the same descriptors. We investigated the predictability of the model by calculating log P(o/w) of four compounds in the test set and found their predicted values to be in good agreement with the experimental values. The QSPR analyses performed on 24 complexes, combining the training and test sets, also provided significant values for the statistical parameters. The solvent medium played an important role in QSPR analysis by increasing the internal predictive ability of the models.

Covalent bond fragmentation suitable to describe solids in the fragment molecular orbital method.

To improve the accuracy of the fragment molecular orbital method (FMO), we introduce a new fragmentation scheme based on using frozen orbitals to describe fractioned bonds. By applying this scheme to a set of polyalanine systems of up to 40 residues for the alpha-helix and beta-strand isomers, we established its accuracy, which is considerably improved compared to the original hybrid orbital projection method used for detaching bonds in FMO. For instance, at the two-body FMO expansion with the 6-311G* basis set, the error was typically reduced 2-4 times, and for 6-31G* the accuracy increase was even larger (10 times in terms of the maximum error). For the Trp-cage protein (PDB file 1L2Y) with many charged residues, a fairly large error was observed, which was shown to become small with a larger fragment size or at the three-body level. Consequently, we applied the new scheme to the adsorption of toluene and phenol on a faujasite zeolite, and we demonstrated that good accuracy can be achieved in reproducing ab initio results.

Comparative Study of Potassium Salt-Loaded MgAl Hydrotalcites for the Knoevenagel Condensation Reaction.

A series of potassium salt-loaded MgAl hydrotalcites were synthesized by wet impregnation of KNO3, KF, KOH, K2CO3, and KHCO3 salts over calcined MgAl hydrotalcite (Mg-Al = 3:1). The samples were characterized by X-ray diffraction, Fourier transform infrared, thermogravimetry-differential thermal analysis, scanning electron microscopy, and N2 absorption-desorption techniques to investigate their structural properties. The results showed formation of well-developed hydrotalcite phase and reconstruction of layered structure after impregnation. The prepared hydrotalcites possess mesopores and micropores having pore diameters in the range of 3.3-4.0 nm and Brunauer-Emmett-Teller surface area 90-207 m2 g-1. Base strengths calculated from Hammett indicator method were found increasing after loading salts, where KOH-loaded hydrotalcite showed base strength in the range of 12.7 < H- < 15, which was found to be the preferred catalyst. Subsequently, KOH loading was increased from 10 to 40% (w/w) and catalytic activity was evaluated for the Knoevenagel condensation reaction at room temperature. Density functional theory calculations show that among all of the oxygen atoms present in the hydrotalcite, the O atom attached to the K atom has the highest basic character. In this study, 10% KOH-loaded hydrotalcite showing 99% conversion and 100% selectivity was selected as the preferred catalyst in terms of base strength, stability, and catalytic efficiency.

Why is otosclerosis of low prevalence in Japanese?

OBJECTIVE: This study aimed to clarify the reasons why clinical otosclerosis, a very common disease among Caucasians, is not prevalent among Japanese. STUDY DESIGN: The incidence, site, activity, and volume of otosclerotic foci were examined in 1011 temporal bone sections from 507 Japanese individuals. SETTING: This study was prepared at the temporal bone laboratory, Fukushima Medical University, Fukushima. RESULTS: Otosclerotic foci were observed in 2.56% of individuals and in 1.48% of the ears. The most common site of involvement was anterior to the oval window region, but this was only in 38.9% of the ears with otosclerotic foci. The otosclerotic foci were not involved in the stapediovestibular articulation or the endosteal layer of the otic capsule in any ears. An active change of the otosclerotic focus was seen in 33.3% of ears with otosclerosis. The volume of otosclerotic foci at the site anterior to the oval window region was less than 0.8 mm3 in 5 out of 7 ears. CONCLUSION: The incidence of histologic otosclerosis among Japanese seemed to be almost the same as that among Caucasians. Three reasons why clinical otosclerosis was not as prevalent among Japanese as among Caucasians are suggested: low incidence of involvement of foci anterior to the oval window, low activity, and small lesion without involvement of the footplate and/or membranous labyrinth of the inner ear.