Relative strengths of Se?N,O interactions: Implications for glutathione peroxidase activity

Natural bond orbital (NBO) studies of model compounds of glutathione peroxidase and its mimics are used to examine the relative strengths of nitrogen and oxygen donor groups in simple models and ω-substituted selenenic acids. Nitrogen-containing groups are generally better donors, but the weak Lewis basicity of the amide nitrogen allows for preferential interaction with the carbonyl oxygen which suggests that the glutamine of the GPX catalytic triad influences activity through an Se?O interaction.     

A study on the structures of the substituted (aminomethyl)lithium and (thiomethyl)lithium compounds

The structures of substituted (aminomethyl)lithium and (thiomethyl)lithium compounds have been examined. Geometric parameters, charge densities, bond orders, dipole moments and heats of formation for all the members of the two series of monomers and dimers of the units LiCN(R)2 and LiCSR where R=H, CH3(Me), C6H5(Ph) have been calculated. The structures of the three complex compounds containing the same units; [[Li(CH2SMe)(THF)]X], [Li2(CH2SPh)2(THF)4] and [Li2(CH2NPh2)2(THF)3] have also been modeled. Geometry optimizations have been performed with the semiempirical PM3 method. The molecular orbital calculations have been carried out by a self-consistent field method using the restricted Hartree-Fock formalism. Comparisons have been made with the corresponding properties of methyl lithium monomer and dimer. The results show that in all of the nitrogen-containing monomers, the C-Li bonds weaken and the Li-C-H(N) angles decrease due to the coordination of lithium with nitrogen. Substitution of hydrogen atoms by methyl or phenyl groups decreases the Li-N coordination. In the sulfur-containing compounds, sulfur behaves similarly to nitrogen but the changes are smaller because the 3p lone-pair orbital of sulfur is higher in energy than the 2p lone-pair of nitrogen. All the dimers of nitrogen/sulfur-containing methyl lithium derivatives form six-membered rings in which the Li-N(S) coordination is greater than the one in the corresponding monomers. Dimerization reactions have been found to be exothermic and the formation of all the dimers is favored. The results obtained for the three complex structures are comparable to the experimental results reported in the literature.Keywords:     

Stereoelectronic control in peptide bond formation. Ab initio calculations and speculations on the mechanism of action of serine proteases.

Ab initio molecular orbital calculations have been performed on the reaction profile for the addition/elimination reaction between ammonia and formic acid, proceeding via a tetrahedral intermediate: NH3 + HCO2H----H2NCH(OH)2----NH2CHO + H2O. Calculated transition state energies for the first addition step of the reaction revealed that a lone pair on the oxygen of the OH group, which is antiperiplanar to the attacking nitrogen, stabilized the transition state by 3.9 kcal/mol, thus supporting the hypothesis of stereoelectronic control for this reaction. In addition, a secondary, counterbalancing stereoelectronic effect stabilizes the second step, water elimination, transition state by 3.1 kcal/mol if the lone pair on the leaving water oxygen is not antiperiplanar to the C-N bond. The best conformation for the transition states was thus one with a lone pair antiperiplanar to the adjacent scissile bond and also one without a lone-pair orbital on the scissile bond oxygen or nitrogen antiperiplanar to the adjacent polar bond. The significance of these stereoelectronic effects for the mechanism of action of serine proteases is discussed.     

Chiral ureas with two electronegative substituents at 1-N: an unusual case of coexisting pyramidal and almost planar 1-N atoms in the same crystal

XRD studies of structure of N-acetoxy-N-methoxyurea and N,N-bis(methoxycarbonyl)-N-methoxyimide have revealed that in N-methoxy-N-X-ureas (X = OAc, Cl, OMe, N(+)C(5)H(5)) the additional shortening of N-OMe bond took place, which arising from an n(O(Me))-sigma*(N-X) anomeric orbital interaction. XRD studies of N-chloro-N-ethoxyurea crystal have revealed the presence of two kinds of anomeric nitrogen configuration in the O-N-Cl group in the form of a pyramidal configuration and a planar configuration for same 1-N nitrogen atom. XRD studies of N-4-chlorobenzoyloxy-N-ethoxyurea have revealed that the degree of pyramidality of the 1-N nitrogen in N-aroyloxy-N-alkoxyureas is tuned by orientation of benzoyl group with respect to the N-O bond, which in turn depends of size of N-alkoxy group.     

A molecular orbital study on the oxidation of hydrogen donor molecules by peroxidase compound II

The electronic characteristics of some hydrogen donor substrate (phenol and aniline derivatives) for peroxidase reaction were calculated with the aid of the CNDO/2 and other methods. These results were compared with the experimental data concerning the rate of oxidation of these compounds by peroxidase and hydrogen peroxide. No simple relationship between the total or frontier electron densities on the oxygen or nitrogen atoms, or the lowest unoccupied orbital energies, and the rate of oxidation was found. It was, however, found that the logarithm of the rate of oxidation for the compounds studied correlates linearly with the highest occupied orbital energies. Based on these results, the mechanism of electron transfer from the substrate to compound II is discussed.     

A geometry optimization and molecular electrostatic potential mapping study of structure-activity relationship for some anti-Alzheimer agents.

Molecular geometries of some substituted (pyrroloamino)pyridines which possess anti-Alzheimer activity were optimized and potential-derived CHelpG point charges were computed using ab initio SCF molecular orbital approach employing the 3-21G basis set. AM1 molecular orbital calculations were performed using these optimized geometries and thus optimized Hybridization. Displacement Charges (HDC) combined with L?wdin charges continuously distributed in three dimension were obtained. Molecular electrostatic potential (MEP) maps of the molecules were obtained in two ways: (i) using the HDC-based model with the help of which MEP minima near the molecules were located, and (ii) using the CHelpG point charges, MEP values on the van der Waals surfaces of the molecules were computed. The MEP maps computed using both the methods have negative MEP regions near the pyridine nitrogen atom which appears to be the main binding site of the molecules with the appropriate receptor. Both electrostatic interaction and lipophilic association between these molecules and the receptor appear to contribute to biological activity.     

Localization of the retinal protonated Schiff base counterion in rhodopsin.

Semiempirical molecular orbital calculations are combined with 13C NMR chemical shifts to localize the counterion in the retinal binding site of vertebrate rhodopsin. Charge densities along the polyene chain are calculated for an 11-cis-retinylidene protonated Schiff base (11-cis-RPSB) chromophore with 1) a chloride counterion at various distances from the Schiff base nitrogen, 2) one or two chloride counterions at different positions along the retinal chain from C10 to C15 and at the Schiff base nitrogen, and 3) a carboxylate counterion out of the retinal plane near C12. Increasing the distance of the negative counterion from the Schiff base results in an enhancement of alternating negative and positive partial charge on the even- and odd-numbered carbons, respectively, when compared to the 11-cis-RPSB chloride model compound. In contrast, the observed 13C NMR data of rhodopsin exhibit downfield chemical shifts from C8 to C13 relative to the 11-cis-RPSB.Cl corresponding to a net increase of partial positive or decrease of partial negative charge at these positions (Smith, S. O., I. Palings, M. E. Miley, J. Courtin, H. de Groot, J. Lugtenburg, R. A. Mathies, and R. G. Griffin. 1990. Biochemistry. 29:8158-8164). The anomalous changes in charge density reflected in the rhodopsin NMR chemical shifts can be qualitatively modeled by placing a single negative charge above C12. The calculated fit improves when a carboxylate counterion is used to model the retinal binding site. Inclusion of water in the model does not alter the fit to the NMR data, although it is consistent with observations based on other methods.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tetraethylorthosilicate as molecular precursor to the formation of amorphous silica networks. A DFT-SCRF study of the base catalyzed hydrolysis

Quantum chemical calculations using density functional theory have been carried out to investigate two chemical pathways for the last step of the hydrolysis of tetraethylorthosilicate (TEOS) in basic catalyzed environment. The two models that are introduced in this study depend on the number of water molecules involved at the base catalyzed hydrolysis. Solution equilibrium geometries of the molecules involved in the transition states, reactants and product complexes of the two chemical pathways were fully optimized at B3LYP level of theory with the standard 6-31+G(d) basis set, modeling solvent effects using a polarizable continuum solvation model (PCM). Both models predict relative low activation energies. However, the model with two water molecules seems to be more adequate to describe the basic hydrolysis. A natural bond orbital (NBO) analysis seems to show that the proton transfer from water to ethoxy group would occur through a large hyperconjugative interaction, LP(O) → σ*(O-H), which is related to the nonbonding oxygen lone pair orbital from ethoxy group with the vicinal σ*(O-H) anti bonding orbital O-H of a water molecule.     

A computational study of the passive mechanisms of eye restraint during head impact trauma

A finite element model of the eye and the orbit was used to examine the hypothesis that the orbital fat provides an important mechanism of eye stability during head trauma. The model includes the globe, the orbital fat, the extra-ocular muscles, and the optic nerve. MRI images of an adult human orbit were used to generate an idealized geometry of the orbital space. The globe was approximated as a sphere 12 mm in radius. The optic nerve and the sclera were represented as thin shells, whereas the vitreous and the orbital fat were represented as nearly incompressible solids of low stiffness. The orbital bone was modelled as a rigid shell. Frontal head impact resulting from a fall onto a hard floor was simulated by prescribing to the orbital bone a triangular acceleration pulse of 200 g (1962 m/s(2)) peak for a duration of 4.5 ms. The results show that the fat provides the crucial passive mechanism of eye restraint. The mechanism is a consequence of the fact that the fat is incompressible and that its motion is restricted by the rigidity of the orbital walls. Thus, the acceleration loads of short duration cannot generate significant distortion of the fat. In contrast, the passive muscles provide little support to the globe. When the connection between the orbital fat and the eye is absent the eye is held mainly by the optic nerve. We discuss the possible role that this loss of contact may have in some cases of the evulsion of the eye and the optic nerve.     

Adsorption of tetracyanoquinodimethane and tetrathiafulvalene on aluminium (100) surface – a first principle study of structural and electronic properties

Possible adsorption configurations and electronic properties, such as charge analysis, density of states, work function and Schottky barrier height of tetracyanoquinodimethane (TCNQ) and tetrathiafulvalene (TTF) on Aluminium (100) surface is studied by using density functional theory methods with local density approximation (LDA), generalised gradient approximation (GGA), PBE and PBE-D2 methods. TCNQ is strongly adsorbed on Al(100) with adsorption energy of ?3.66?eV. The charge is transferred from Al(100) to TCNQ and charge transfer occurs mainly through cyano group of TCNQ. Adsorption on Al(100) surface leads to downshift in energy difference between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of TCNQ by 2.5?eV as result of hybridisation of p orbital of carbon and nitrogen atoms of TCNQ and p orbital of surface Al atoms. Compared to TCNQ adsorption, TTF adsorption on Al(100) surface is having less adsorption energy and type of interaction is physisorption. The charge transfer from TTF to Al(100) surface leads to decrease in work function of Al by 0.24?eV. The n-type Schottky barrier height of TCNQ/Al(100) and p-type Schottky barrier height of TTF/Al(100) is 0.68eV and 1.97?eV, respectively showing that TCNQ and Al(100) are suitable for organic photovoltaic and electrochemical applications.     

The direct effect of intraorbital pressure on orbital growth in the anophthalmic piglet.

Tissue expanders placed within the orbit can have a positive effect on orbital and ipsilateral midfacial growth. To date, there is no precise method for controlling and monitoring expansion to induce normal growth in the developing facial skeleton. The present study was undertaken to determine the optimal physiologic pressure required to stimulate normal orbital growth and to determine whether above-normal growth could be achieved with higher intraorbital pressures. Using a neonatal swine model, an accurate method of monitoring intraorbital pressure, precisely controlling intraorbital expansion, and achieving normal orbital growth was explored. Sixteen male, 3-week-old Yorkshire piglets were randomly divided into three surgical groups. In each group, the left orbit was the experimental side, and the contralateral right orbit served as an untreated control. Group 1 (n = 6) underwent enucleation only. Group 2 (n = 5) underwent enucleation and orbital expansion at a near-normal physiologic pressure of 20 mmHg. Group 3 (n = 5) underwent enucleation and orbital expansion at a supernormal pressure of 60 mmHg. Spherical tissue expanders (10 cc) with a separate injection port were utilized as the orbital expanders. Pressure was monitored by an electronic manometer that was calibrated daily. Morphology of the orbits was documented by photography, the dimensions of the orbits were quantitated by three-dimensional mechanical digitization, and orbital volumes were calculated. In the unexpanded, anophthalmic control group, a significant reduction in radial growth after evisceration was seen. In group 2, the orbit stimulated with a consistent pressure of 20 mmHg, just above the physiologic normal pressure of 17 mmHg, showed an increase in radial dimension of 8 percent compared with the unoperated side. In the high-pressure group of 60 mmHg, an increase of 16 percent in the radius was observed over the 4-week period. This led to a corresponding increase in orbital volumes with increased pressure. Utilizing a paired t test, these differences in the radial and volumetric growth of the orbit were statistically significant (p < 0.005). The results obtained demonstrated a direct relationship between intraorbital pressure and the growth of the bony orbit in the radial dimension. On the basis of this study, we concluded that orbital expansion maintained at normal physiologic pressure can stimulate normal orbital growth in the neonatal facial skeleton. In addition, application of above-normal pressures for expansion can induce accelerated orbital growth.     

Stereochemical aspects of peptide hydrolysis catalyzed by serine proteases of the chymotrypsin type

The steric course of peptide hydrolysis catalyzed by serine proteases has been studied on the basis of the available, extensive structural data and taking into account the stereoelectronic theory of Deslongchamps (Heterocycles, 7, 1271 (1977)). These studies allowed elucidation of the structure of intermediates, in particular of the tetrahedral intermediate, and of the main structural events taking place during catalysis. They reveal a difficulty inherent in the generally accepted mechanism of peptide hydrolysis: protonation of the leaving nitrogen in the configuration arising from nucleophilic attack of Ser-195 on the carbonyl carbon cannot take place internally from His-57. Two alternative mechanisms are discussed which are compatible with all implications of the stereoelectronic theory. The main features of the more probable mechanism are: (i) a conformational change allowing the imidazole ring of His-57 to occupy two distinct positions; in one position a proton is abstracted from O^γ of Ser-195, and in the other this proton is donated to the leaving nitrogen; (ii) a configurational change (inversion) of the pyramidal leaving nitrogen reorienting the lone-pair orbital developed during nucleophilic attack; in one orientation CO bond breaking, and in the other CN bond breaking, is allowed. This inversion process confers on the nitrogen the property of a switch controlling the breakdown of the tetrahedral intermediate.     

Drug-metal interactions: spectroscopic studies of copper hydantoin complexes.

The preparation and spectral properties of copper(II) complexes of two hydantoins are reported. Complexes of the general formula Cu(hyd)2(py)2, where hyd = phenytoin or nirvanol; and py = pyridine were prepared and characterized by infrared and ESR. Spectral data show that the copper atom is bound to the nitrogen atom of the hydantoin anion and to the nitrogen atom of the pyridine molecule to form 2:2:1 hydantoin:pyridine:copper complexes. The ESR data indicate that both complexes have tetragonal symmetry (g11 greater than g perpendicular greater than g e) with the unpaired electron in the d x2-y2 orbital.     

An electron spin resonance investigation and molecular orbital calculation of the anion radical intermediate in the enzymatic cis-trans isomerization of furylfuramide, a nitrofuran derivative of ethylene

The enzymatic cis-trans isomerization of nitrofuran derivatives has been proposed to occur via the formation of a radical anion intermediate. ESR investigations, in conjunction with intermediate neglect of differential overlap (INDO) molecular orbital calculations, support this concept by demonstrating the enzymatic generation of cis and trans radical anions of 3-(5-nitro-2-furyl)-2-(2-furyl) acrylamide. The INDO calculations further indicate that the rotational barrier between the cis and trans anion radicals of this compound is only 5--10 kcal/mol, whereas a 70 kcal/mol barrier exists for the parent geometric isomers. Hyperfine splitting constants for the cis-trans conformers have been assigned on the basis of INDO calculations. Surprisingly, only the nitrogen hyperfine splitting of the nitro group is distinguishably different in the two conformers, a result which is not inconsistent with the INDO calculations.     

How do aldehyde side products occur during alkene epoxidation by cytochrome P450? Theory reveals a state-specific multi-state scenario where the high-spin component leads to all side products

A theoretical study of alkene epoxidation, by the high-valent iron-oxo species (Compound I) of cytochrome P450, reveals a multi-state scenario in which the different products are generated in a state specific manner. All the low-spin doublet state processes are effectively concerted epoxide producing pathways. By contrast, all the high-spin quartet processes are stepwise and either lead to epoxide that does not conserve the isomeric identity of the alkene (cis or trans), or/and to by-products such as suicidal complexes and aldehydes. The product/state inventory is the following: (a) The epoxide with conserved alkene stereochemistry is generated from the low-spin doublet states of Compound I in a nonsynchronous but effectively concerted pathways that involve carbon radical (with Fe(III) and Fe(IV)) and cationic intermediates. (b) The epoxide with scrambled alkene stereochemistry is obtained from the quartet high-spin radical intermediate (with Fe(IV)). (c) The suicidal complex, with a C-N bond between the alkene and the porphyrin, is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding Fe-N orbital made from dxy and nitrogen sigma-hybrids). (d) The aldehyde by-product is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding O-Fe-S orbital made from dz2 and the oxo and sulfur sigma-hybrids). Factors controlling the competition between these processes are discussed.     

Nitrogen fixation and the mass balances of carbon and nitrogen in ecosystems

Ecosystems with high rates of nitrogen fixation often have high loss rates through leaching or possibly denitrification. However, there is no formal theoretical context to examine why this should be the case nor of how nitrogen accumulates in such open systems. Here, we propose a simple model coupling nitrogen inputs and losses to carbon inputs and losses. The nitrogen balance of this model system depends on plant (nitrogen fixer) growth rate, its carrying capacity, N fixed/C fixed, residence time of nitrogen and carbon in biomass, litter decay rate, litter N/C, and fractional loss rate of mineralized nitrogen. The model predicts the requirements for equilibrium in a nitrogen-fixing system, and the conditions on nitrogen fixation and losses in order for the system to accumulate nitrogen and carbon. In particular, the accumulation of nitrogen and carbon in a nitrogen-fixing system depend on an interaction between residence time in vegetation and litter decay rate in soil. To reflect a possible increased uptake of soil nitrogen and decreased respiratory cost of symbiotic nitrogen fixers, the model was then modified so that fixation rate decreased and growth rate increased as nitrogen capital accumulated. These modifications had only small effects on carbon and nitrogen accumulation. This suggests that switching from uptake of atmospheric nitrogen to mineral soil nitrogen as nitrogen capital accumulates simply results in a trade-off between energetic limitations and soil nitrogen limitations to carbon and nitrogen accumulation. Experimental tests of the model are suggested.     

Calculation of the g-factors of hemoproteins with the crystal field theory. Development of a 3-term model

A 3-term crystal field model is used for the calculation of the magnetic properties of ferric hemoproteins. This model includes the high spin term (6A1), the low spin term (2T2) and the quartet term (4T1). The pertubation matrix between these 3 terms caused by spin orbit coupling and ligand fields of cubic, axial and rhombic symmetry are evaluated. The g-factor of the low spin cytochrome P-450 LM2 from rabbit liver are calculated using this 3-term model and the results are compared with those from the usual 1-term model. Contrary to the 1-term model, no orbital moment correction factor is necessary. That means that the orbital moment correction factor with value > 1 simulates some term interaction, predominantly with the quartet term. The g-factors of the high spin cytochrome P-450 LM4 were also calculated by means of the 3-term model and compared with a spin hamilton treatment. A good agreement between the spin hamilton parameters derived from the experimental g-factors and those calculated by the 3-term model were obtained. For hemoproteins with strongly mixed spin states the 3-term model is also useful, contrary to 1-term models or spin hamiltonians which are completely incorrect. The 3-term model is a minimal model to describe all typical magnetic properties of low spin and high spin ferric hemoproteins with the smallest number of terms.