Direct ab initio dynamics studies of the hydrogen abstraction reactions of hydrogen atom with n-propyl radical and isopropyl radical

The kinetics of the hydrogen abstraction reactions of hydrogen atom with n-propyl radical and isopropyl radical were studied using the direct ab initio dynamics approach. BHandHLYP/cc-pVDZ method was employed to optimize the geometries of stationary points as well as the points on the minimum energy path (MEP). The energies of all the points for the two reactions were further refined at the QCISD(T)/cc-pVTZ level of theory. No barrier was found at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory for both reactions. The forward and reverse rate constants were evaluated with both canonical variational transition state theory (CVT) and microcanonical variational transition state theory ( VT) in the temperature range of 300–2,500 K. The fitted three-parameter Arrhenius expression of the calculated CVT rate constants at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory are k^CVT (n – C₃H₇)=1.68×10^–14 T^0.84 e^(319.5/T) cm³ molecule^–1 s^–1 and k^CVT (iso-C₃H₇)=4.99×10^–14 T^0.90 e^(159.5/T) cm³ molecule^–1 s^–1 for reactions of n-C₃H₇ + H and iso-C₃H₇ + H, respectively, which are in good agreement with available literature data. The variational effects were analysed.Figure Comparison of the calculated forward rate constants at the QCISD(T)/cc-pVTZ//BHandHLYP/cc-pVDZ level of theory and the available experimental and theoretical data of the reaction vs 1,000/T for the two reactions.     

Interaction energies in non-covalently bound intermolecular complexes derived using the subsystem formulation of density functional theory

Interaction energies for a representative sample of 39 intermolecular complexes are calculated using two computational approaches based on the subsystem formulation of density functional theory introduced by Cortona (Phys. Rev. B 44:8454, 1991), adopted for studies of intermolecular complexes (Wesolowski and Weber in Chem. Phys. Lett. 248:71, 1996). The energy components (exchange-correlation and non-additive kinetic) expressed as explicit density functionals are approximated by means of gradient-free- (local density approximation) of gradient-dependent- (generalized gradient approximation) approximations. The sample of the considered intermolecular complexes was used previously by Zhao and Truhlar to compare the interaction energies derived using various methods based on the Kohn-Sham equations with high-level quantum chemistry results considered as the reference. It stretches from rare gas dimers up to strong hydrogen bonds. Our results indicate that the subsystem-based methods provide an interesting alternative to that based on the Kohn-Sham equations. Local density approximation, which is the simplest approximation for the relevant density functionals and which does not rely on any empirical data, leads to a computational approach comparing favorably with more than twenty methods based on the Kohn-Sham equations including the ones, which use extensively empirical parameterizations. For various types of non-bonding interactions, the strengths and weaknesses of gradient-free and gradient-dependent approximations to exchange-correlation and non-additive kinetic energy density functionals are discussed in detail.     

Conformational preferences of 1,4,7-trithiacyclononane: a molecular mechanics and density functional theory study

Conformational preferences of 1,4,7-trithiacyclononane were studied using a highly efficient sampling technique based on local nonstochastic deformations and the MM2(91) force field. The results show that conformers that the molecule adopts in the crystal state were found to be low-energy conformers (LECs) within 5 kcal mol(-1) of the global minimum. A conformation with C1 symmetry was the global minimum and the C3 and C2 conformations were calculated to be 0.03 and 1.78 kcal mol(-1) higher in energy, respectively. The structures were further minimized using Density Functional Theory (DFT) calculations with two different functionals. The C2 and the C1 conformations were found to be LECs with the C3 conformation more than 4.0 kcal mol(-1) above the global minimum. The relative energies and structural ordering obtained using the BP86 functional are in agreement with the previously reported relative energies calculated using second-order Moller-Plesset (MP2) ab initio calculations. With the energy ordering being dependent on the molecular mechanics force field used, the approach of MM-->DFT (searching exhaustively the available conformational space at the MM level followed by generating the energy ordering through DFT calculations) appears to be appropriate for thiacrown ethers.     

Characterization of the active site of catalytically inactive forms of [NiFe] hydrogenases by density functional theory

The inactive forms, unready (Ni-A, Ni-SU) and ready (Ni-B), of NiFe hydrogenases are modeled by examining the possibility of hydroxo, oxo, hydroperoxo, peroxo, and sulfenate groups in active-site models and comparing predicted IR frequencies and g tensors with those of the enzyme. The best models for Ni-A and Ni-SU have hydroxo (μ-OH) bridges between Fe and Ni and a terminal sulfenate [Ni–S(=O)Cys] group, although a hydroperoxo model for Ni-A is also quite viable, whereas the best model for Ni-B has only a μ-OH bridge. In addition, a mechanism for the activation of unready hydrogenase is proposed on the basis of the relative stabilities of sulfenate models versus peroxide models.     

Prototropic tautomerism of imidazolone in aqueous solution: a density functional approach using the combined discrete/self-consistent reaction field (SCRF) models

A systematic investigation of the proton transfer in the keto-amino/enol tautomerization of imidazolone was undertaken. Calculations in aqueous solution were performed using both combined discrete/self-consistent reaction field (SCRF) and SCRF methods. Complexes containing one to three water molecules around the hydrophilic site of imidazolone were used for the combined discrete/SCRF calculations. The DFT results predict that the barrier height for non-water-assisted intramolecular proton transfer is very high (214.8 kJmol^–1). Hydrogen bonding between imidazolone and the water molecule(s) will dramatically lower the barrier by a concerted multiple proton transfer mechanism. The proton transfer process through a eight-member ring formed by imidazolone and two water molecules is found to be more efficient and the calculated barrier height is ca. 61 kJmol^–1.Figure DFT calculations in aqueous solution predict the H-bonding between imidazolone(IZ) and the water molecule(s) will dramatically lower the tautomeric barrier by a concerted multiple proton transfer mechanism, in which an eight-member ring structure formed by IZ and 2H₂O is found to be more efficient and the barrier is 60.8 kJ mol^–1, much less than 214.8 kJ mol^–1 in the non-water-assisted mechanism.     

Insight into the copper coordination environment in the prion protein through density functional theory calculations of EPR parameters

Density functional theory (DFT) calculations of Cu(II) electron paramagnetic resonance (EPR) parameters for the octarepeat unit of the prion protein were conducted. Model complexes were constructed and optimized using the crystal structure of the octarepeat unit of the prion protein. Copper g and A tensors and nitrogen hyperfine and quadrupole coupling constants were calculated using DFT. Solvent effects were incorporated using the conductor-like screening model as well as through the inclusion of explicit water molecules. Calculations using the model with an additional axial water molecule added to the coordination sphere of the Cu(II) metal center give the best qualitative agreement for the copper g and A tensors. The S-band experimental EPR spectra were interpreted in light of the DFT calculations of the directly coordinated nitrogen hyperfine coupling constants which indicate that the three directly coordinated nitrogen atoms in the octarepeat unit are not equivalent. These results demonstrate that DFT calculations of EPR parameters can provide important insight with respect to the structural interpretation of experimental EPR data. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid

N-acetylcysteine has been widely used as an antioxidant in vivo and in vitro. Its reaction with four oxidant species has therefore been examined. N-acetylcysteine is a powerful scavenger of hypochlorous acid (H---OCl); low concentrations are able to protect ₁-antiproteinase against inactivation by HOCl. N-acetylcysteine also reacts with hydroxyl radical with a rate constant of 1.36 × 10¹⁰ M⁻¹s⁻¹, as determined by pulse radiolysis. It also reacts slowly with H₂O₂, but no reaction of N-acetylcysteine with superoxide (O₂⁻) could be detected within the limits of our assay procedures.     

Conformations of adducts formed between the genotoxic benzo[a]pyrene-7,8-dione and nucleosides studied by density functional theory

Benzo[a]pyrene (BP) is a widely distributed environmental pollutant that is metabolized by mammalian cells to a variety of genotoxic and carcinogenic intermediates that form covalent adducts with cellular DNA. One such pathway involves the metabolic activation of BP by members of the aldo-keto-reductase (AKR) family of enzymes to the highly reactive ortho-quinone, benzo[a]pyrene-7,8-dione (BPQ). This compound has been reported to react with the 2'-deoxynucleosides, dA and dG, under physiological conditions. Four BPQ-dG adducts and two -dA adducts were identified by mass spectrometry and NMR methods [Balu et al. (2004) Chem. Res. Toxicol. 17, 827-838]. However, the detailed conformations and absolute configurations around the linkage site have not been resolved. In order to determine the full conformations of these purine adducts, we carried out quantum mechanical geometry optimization using density functional theory. In the case of the BPQ-guanine adducts, six possible structures, each of which consists of two isomers, were identified. However, in the case of the adenine adducts, only four isomers were identified. The results suggest that stereoisomeric adduct pairs are expected to adopt opposite orientations with respect to the 5'-->3' direction of the modified DNA strands. The stereochemistry-dependent variations in adduct orientation may produce different biological effects, as has been observed in the case of DNA adducts derived from other metabolites of polycyclic aromatic hydrocarbons.     

Density functional theory studies of oxygen and carbonate binding to a dicopper patellamide complex

In this work we present results of density functional theory (DFT) calculations on dicopper patellamides and their affinity for molecular oxygen and carbonate. Patellamides are cyclic octapeptides that are produced by a cyanobacterium, and may show promise as therapeutics. Thus, carbonate binding to a dicopper patellamide center gives a stable cyclic octapeptide with a twist of almost 90°. The system exists in close-lying open-shell singlet and triplet spin states with two unpaired electrons in orthogonal σ^∗ orbitals on each metal center. Subsequently, we replaced carbonate with dioxygen and found a stable Cu₂(μ-O)₂ diamond shaped patellamide core. In this structure the original dioxygen bond is significantly weakened to essentially a single bond, which should enable the system to transfer these oxygen atoms to substrates. We predicted the IR and Raman spectra of the Cu₂(μ-O)₂ diamond shaped patellamide structure using density functional theory and found a considerable isotope effect on the O-O stretch vibration for ¹⁶O₂ versus ¹⁸O₂ bound structures. Our studies reveal that carbonate forms an extremely stable complex with dicopper patellamide, but that additional molecular oxygen to this system does not give a potential oxidant. Therefore, it is more likely that carbonate prepares the system for dioxygen binding by folding it into the correct configuration followed in the proposed catalytic cycle by a protonation event preceding dioxygen binding to enable the system to reorganize to form a stable Cu₂(μ-O)₂-patellamide cluster. Alternatively, carbonate may act as an inhibitor that blocks the catalytic activity of the system. It is anticipated that the Cu₂(μ-O)₂-patellamide structure is a potential active oxidant of the dicopper patellamide complex.     

Synthesis, crystal structures and density functional theory study of dimeric copper(II) complexes of a tridentate Schiff-base ligand

Oxalate- or 4,4′-bipyridine-bridged dimeric copper(II) complexes, [Cu₂L₂(μ-ox)] (1) and [Cu₂L₂(μ-bipy)](BF₄)₂ (2) [where ox = oxalate, bipy = 4,4′-bipyridine, HL = N-(1H-pyrrol-2-ylmethylene)-2-pyridineethanamine, L⁻ = HL−H⁺], have been synthesised and characterised by elemental analysis, IR, UV-Vis and single crystal X-ray diffraction. Crystal structure determinations carried out on 1 and 2 reveal that 1 is an oxalate-bridged centrosymmetrical square pyramidal dimeric copper(II) complex while 2 is a 4,4′-bipyridine-bridged non-centrosymmetric square planar dinuclear copper(II) complex. Comparison of the optimised geometries with the corresponding crystal structures suggests that the B3LYP/LANL2DZ level can reproduce the structures of 1 and 2 on the whole. The electronic spectra of 1 and 2 predicted by B3LYP/LANL2DZ method show some blue shifts compared with their experimental data. Thermal analysis carried out on 1 shows that there is only one exothermal peak at about 260 °C and the residue is presumably Cu₂O₄N₆.     

A density functional theory study on the role of His-107 in arylamine N-acetyltransferase 2 acetylation

Arylamine N-acetyltransferases (NATs, EC 2.3.1.5) catalyze an acetyl group transfer from acetyl coenzyme A (AcCoA) to primary arylamines, and are responsible for the biotransformation and metabolism of drugs, carcinogens, etc. Structure analysis revealed that His-107 was likely the residue accountable for mediating acetyl transfer. We have examined the full catalytic mechanism of this system by means of DFT method. The results indicate that if the acetyl group directly transferred from the donor, p-nitrophenyl acetate, to the acceptor, cysteine, the high activation energy will be a great hindrance. These energies have dropped a little in a range of 20-25 kJ/mol when His-107 is assisting the transfer process. However, when protonated His-107 is mediating the reaction, the activation energies have dropped about 70-85 kJ/mol. Our calculations strongly support an enzymatic acetylation mechanism that experiences a thiolate-imidazolium pair, which have verified the presumption from experiments.     

On the oxidation of alkyl and aryl sulfides by [(Me3TACN)MnO(OH)2]: A density functional study

Density functional theory suggests that the formal 2-electron oxidation of sulfides, RR′S, to sulfoxides, by the model Mn^VO catalyst, [(TACN)Mn^V O(OH)₂]⁺, proceeds in two quite distinct 1-electron steps. Transfer of the first electron is barrierless and generates a sulfur radical cation, antiferromagnetically coupled to a Mn^IV centre via a covalent μ-oxo bridge. The second electron-transfer step is accompanied by migration of the oxygen atom to the sulfur centre, and is rate-determining. The absence of a barrier in the first step, where a sulfur radical is formed, means that the presence of electron-donating or withdrawing substituents on the sulfide has only a minor impact on the rate of reaction.     

Syntheses, characterization, density functional theory calculations, and activity of tridentate SNS zinc pincer complexes

A series of tridentate SNS ligand precursors were metallated with ZnCl₂ to give new tridentate SNS pincer zinc complexes. The zinc complexes serve as models for the zinc active site in liver alcohol dehydrogenase (LADH) and were characterized with single crystal X-ray diffraction, ¹H, ¹³C, and HSQC NMR spectroscopies and electrospray mass spectrometry. The bond lengths and bond angles of the zinc complexes correlate well to those in horse LADH. The zinc complexes feature SNS donor atoms and pseudotetrahedral geometry about the zinc center, as is seen for liver alcohol dehydrogenase. The SNS ligand precursors were characterized with ¹H, ¹³C, and HSQC NMR spectroscopies and cyclic voltammetry, and were found to be redox active. Gaussian calculations were performed and agree quite well with the experimentally observed oxidation potential for the pincer ligand. The zinc complexes were screened for the reduction of electron poor aldehydes in the presence of a hydrogen donor, 1-benzyl-1,4-dihydronicotinamide (BNAH). The zinc complexes enhance the reduction of electron poor aldehydes. Density functional theory calculations were performed to better understand why the geometry about the zinc center is pseudo-tetrahedral rather than pseudo-square planar, which is seen for most pincer complexes. For the SNS tridentate pincer complexes, the data indicate that the pseudo-tetrahedral geometry was 43.8 kcal/mol more stable than the pseudo-square planar geometry. Density functional theory calculations were also performed on zinc complexes with monodentate ligands and the data indicate that the pseudo-tetrahedral geometry was 30.6 kcal/mol more stable than pseudo-square planar geometry. Overall, the relative stabilities of the pseudo-tetrahedral and pseudo-square planar systems are the same for this coordination environment whether the ligand set is a single tridentate SNS system or is broken into three separate units. The preference of a d¹⁰ Zn center to attain a tetrahedral local environment trumps any stabilization gained by removal of constraints within the ligand set.     

Determination of the absolute configurations of chiral organometallic complexes via density functional theory calculations of their vibrational circular dichroism spectra: The chiral chromium tricarbonyl complex of N-pivaloyl-tetrahydroquinoline

The racemate of the chiral tricarbonyl-η⁶-arene-chromium(0) complex, tricarbonyl-η⁶-N-pivaloyl-tetrahydroquinoline-chromium(0), 1, has been synthesized and resolved using chromatography on a (R,R)-Whelk-O1 column. The Absolute Configuration (AC) of 1 has been determined using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of 1 has been predicted using the Stephens equation for vibrational rotational strengths, implemented using density functional theory (DFT) in the gaussian program. Using the B3PW91 functional and the 6-311++G (2d,2p) basis set, the predicted VCD spectrum of S-1 is in excellent agreement with the experimental VCD spectrum of (+)-1, leading unambiguously to the AC S-(+). It is concluded that VCD is a useful technique for determining the ACs of chiral organometallic complexes, given the use of optimum functionals and basis sets.     

The role of glutathione in cadmium ion detoxification: coordination modes and binding properties--a density functional study

In this investigation the reduced form of glutathione molecule (GSH) was considered as a model in the coordination chemistry of Cd²⁺ and group thiol-containing peptides. Three different forms of GSH, corresponding to the prevalent ones in gas-phase and in aqueous solution, were taken into account in the metallation process. The obtained complexes were characterized at the density functional B3LYP level with the purpose to give better insight in the chelation mechanism of GSH with heavy metal ions in living organisms. Solvent effects, whether with explicit water molecules or with polarizable continuum model (PCM), were considered on the most stable cadmium-complexes obtained by every GSH charged species examined.     

Comparison of the electronic properties,and thermodynamic and kinetic parameters of the aquation of selected platinum(II) derivatives with their anticancer IC<Subscript>50</Subscript> indexes

Three potential anticancer agents {trans-[PtCl(2)(NH(3))(thiazole)], cis-[PtCl(2)(NH(3))(piperidine)], and PtCl(2)(NH(3))(cyclohexylamine) (JM118)} were explored and compared with cisplatin and the inactive [PtCl(dien)](+) complex. Basic electronic properties, bonding and stabilization energies were determined, and thermodynamic and kinetic parameters for the aquation reaction were estimated at the B3LYP/6-311++G(2df,2pd) level of theory. Since the aquation process represents activation of these agents, the obtained rate constants were compared with the experimental IC(50) values for several tumor cells. Despite the fact that the processes in which these drugs are involved and the way in which they affect cells are very complex, some correlations can be deduced.     

Identification of the sites of hydroxyl radical reaction with peptides by hydrogen/deuterium exchange: prevalence of reactions with the side chains

Hydroxyl radical-effected protium/deuterium ((1)H/(2)H) exchange into the C-H bonds present in peptides has been used to identify the site of hydrogen atom abstraction by hydroxyl radical. Radiolysis of anaerobic, N(2)O-saturated D(2)O solutions containing peptide and dithiothreitol generates a hydroxyl radical that mediates (1)H/(2)H exchange into the side chains of peptides of up to 66 atom % excess (2)H. The (1)H/(2)H exchange is determined by measuring the isotope ratio, [M + H + 1](+)/[M + H](+), of the peptide using electrospray ionization-mass spectrometry. The (1)H/(2)H exchange within each residue of the peptide was determined by measuring the isotope ratio of each isolated dansyl amino acid following hydrolysis and derivatization. Generation of 0.40 mM hydroxyl radical effected (1)H/(2)H exchange into each of the five different residues of (Ala(2))-leucine enkephalin (YAGFL). The propensity of the residues to undergo exchange was L > Y > A congruent with F > G, independent of whether they were radiolyzed separately or as the peptide. The minimal exchange into glycine suggests that reaction of hydroxyl radical with the side chain hydrogens predominates over reaction with the polypeptide alpha-hydrogens. The ability of radiolysis to effect (1)H/(2)H exchange into a larger peptide, SNEQKACKVLGI, was also demonstrated.     

Deformability of Fe(II)CO and Fe(III)CN groups in heme protein models: nonlocal density functional theory calculations

 High-quality nonlocal density functional calculations have been carried out on the deformability of Fe(II)CO and Fe(III)CN units in model compounds of heme proteins. The results confirm our previous finding with a local functional that the Fe(II)CO unit is significantly deformable with respect to tilting and bending. This deformability stems in large part from a large, negative interaction constant between the FeC tilt and FeCO bend coordinates. The Fe(III)CN unit is also significantly deformable, but in this case the deformability results from a very small Fe(III)CN bend force constant and the ability of the cyano nitrogen to act as a hydrogen bond acceptor. The prediction that the energetic penalty associated with deforming the Fe(II)CO unit is relatively modest indicates that such deformations are unlikely to be the dominant contributor to myoglobin's discrimation against CO in favor of O₂. Received, accepted: 16 June 1997