Kinetics of 1,6-hydrogen migration in alkyl radical reaction class

The kinetics of the 1,6-intramolecular hydrogen migration in the alkyl radical reaction class has been studied using the reaction class transition state theory (RC-TST) combined with the linear energy relationship (LER) and the barrier height grouping (BHG) approach. The RC-TST/LER, where only reaction energy is needed, and RC-TST/BHG, where no other information is needed, are found to be promising methods for predicting rate constants for any reaction in the 1,6-intramolecular H migration in alkyl radicals reaction class. Direct comparison with available experimental data indicates that the RC-TST/LER, where only reaction energy is needed, can predict rate constants for any reaction in this reaction class with satisfactory accuracy

Intramolecular hydrogen transfer reactions of thiyl radicals from glutathione: formation of carbon-centered radical at Glu, Cys and Gly

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Research in Toxicology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/tx3000494Glutathione thiyl radicals (GS•) were generated in H2O and D2O by either exposure of GSH to AAPH#, photoirradiation of GSH in the presence of acetone, or photoirradiation of GSSG. Detailed interpretation of the fragmentation pathways of deuterated GSH and GSH-derivatives during mass spectrometry analysis allowed us to demonstrate that reversible intramolecular H-atom transfer reactions between GS• and C-H bonds at Cys[αC], Cys[βC], and Gly[αC] are possible

Critical evaluation of the potential energy surface of the CH3 + HO2 reaction system

International audienceThe CH3 + HO2 reaction system was studied theoretically by a newly developed, HEAT345-(Q) method based CHEAT1 protocol and includes the combined singlet and triplet potential energy surfaces. The main simplification is based on the CCSDT(Q)/cc-pVDZ calculation which is computationally inexpensive. Despite the economic and black-box treatment of higher excitations, the results are within 0.6 kcal/mol of the highly accurate literature values. Furthermore, the CHEAT1 surpassed the popular standard composite methods such as CBS-4M, CBS-QB3, CBS-APNO, G2, G3, G3MP2B3, G4, W1U, and W1BD mainly due to their poor performance in characterizing transition states (TS). For TS structures, various standard DFT and MP2 method have also been tested against the resulting CCSD/cc-pVTZ geometry of our protocol. A fairly good agreement was only found in the cases of the B2PLYP and BHandHLYP functionals, which were able to reproduce the structures of all TS studied within a maximum absolute deviation of 7%. The complex reaction mechanism was extended by three new low lying reaction channels. These are indirect water elimination from CH3OOH resulted formaldehyde, H2 elimination yielded methylene peroxide, and methanol and reactive triplet oxygen were formed via H-shift in the third channel. CHEAT1 protocol based on HEAT345-(Q) method is a robust, general, and cheap alternative for high accurate kinetic calculations

Rate and Equilibrium Constant of the Reaction of 1-Methylvinoxy Radicals with O2: CH3COCH2 + O2 <-> CH3COCH2O2

The reaction of 1-methylvinoxy radicals, CH3COCH2, with molecular oxygen has been investigated by experimental and theoretical methods as a function of temperature (291-520 K) and pressure (0.042-10 bar He). Experiments have been performed by laser photolysis coupled to a detection of 1-methylvinoxy radicals by laser-induced fluorescence LIF. The potential energy surface calculations were performed using ab inito molecular orbital theory at the G3MP2B3 and CBSQB3 level of theory based on the density function theory optimized geometries. Derived molecular properties of the characteristic points of the potential energy surface were used to describe the mechanism and kinetics of the reaction under investigation. At 295 K, no pressure dependence of the rate constant for the association reaction has been observed: k1,298K = (1.18 ± 0.04) × 10-12 cm3 s-1. Biexponential decays have been observed in the temperature range 459-520 K and have been interpreted as an equilibrium reaction. The temperature-dependent equilibrium constants have been extracted from these decays and a standard reaction enthalpy of Hr,298K = -105.0 ± 2.0 kJ mol-1 and entropy of Sr,298K = -143.0 ± 4.0 J mol-1 K-1 were derived, in excellent agreement with the theoretical results. Consistent heats of formation for the vinoxy and the 1-methylvinoxy radical as well as their O2 adducts are recommended based on our complementary experimental and theoretical study Hf,298K = 13.0 ± 2.0, -32. 9± 2.0, -85.9 ± 4.0, and -142.1 ± 4.0 kJ mol-1 for CH2CHO, CH3COCH2 radicals, and their adducts, respectively

A hidden active site in the potential drug target Mycobacterium tuberculosis dUTPase is accessible through small-amplitude protein conformational changes

dUTPases catalyze the hydrolysis of dUTP into dUMP and pyrophosphate to maintain the proper nucleotide pool for DNA metabolism. Recent evidence suggests that dUTPases may also represent a selective drug target in mycobacteria because of the crucial role of these enzymes in maintaining DNA integrity. Nucleotide-hydrolyzing enzymes typically harbor a buried ligand-binding pocket at interdomain or intersubunit clefts, facilitating proper solvent shielding for the catalyzed reaction. The mechanism by which substrate binds this hidden pocket and product is released in dUTPases is unresolved because of conflicting crystallographic and spectroscopic data. We sought to resolve this conflict by using a combination of random acceleration molecular dynamics (RAMD) methodology and structural and biochemical methods to study the dUTPase from Mycobacterium tuberculosis. In particular, the RAMD approach used in this study provided invaluable insights into the nucleotide dissociation process that reconciles all previous experimental observations. Specifically, our data suggest that nucleotide binding takes place as a small stretch of amino acids transiently slides away and partially uncovers the active site. The in silico data further revealed a new dUTPase conformation on the pathway to a relatively open active site. To probe this model, we developed the Trp21 reporter and collected crystallographic, spectroscopic, and kinetic data that confirmed the interaction of Trp21 with the active site shielding C-terminal arm, suggesting that the RAMD method is effective. In summary, our computational simulations and spectroscopic results support the idea that small loop movements in dUTPase allow the shuttlingof the nucleotides between the binding pocket and the solvent

Formation Mechanism of Benzo(a)pyrene: One of the Most Carcinogenic Polycyclic Aromatic Hydrocarbons (PAH)

The formation of polycyclic aromatic hydrocarbons (PAHs) is a strong global concern due to their harmful effects. To help the reduction of their emissions, a crucial understanding of their formation and a deep exploration of their growth mechanism is required. In the present work, the formation of benzo(a)pyrene was investigated computationally employing chrysene and benz(a)anthracene as starting materials. It was assumed a type of methyl addition/cyclization (MAC) was the valid growth mechanism in this case. Consequently, the reactions implied addition reactions, ring closures, hydrogen abstractions and intramolecular hydrogen shifts. These steps of the mechanism were computed to explore benzo(a)pyene formation. The corresponding energies of the chemical species were determined via hybrid density funcional theory (DFT), B3LYP/6-31+G(d,p) and M06-2X/6-311++G(d,p). Results showed that the two reaction routes had very similar trends energetically, the difference between the energy levels of the corresponding molecules was just 6.13 kJ/mol on average. The most stable structure was obtained in the benzo(a)anthracene pathway