How is methane formed and oxidized reversibly when catalyzed by Ni-containing methyl-coenzyme M reductase?

Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation and has recently been observed to also be able to catalyze the reverse reaction, the anaerobic oxidation of methane. The forward reaction has been extensively studied theoretically before and was found to consist of two steps. The first step is rate-limiting and the second step was therefore treated at a lower level. For an accurate treatment of the reverse reaction, both steps have to be studied at the same level. In the present paper, the mechanisms for the reversible formation and oxidation of methane catalyzed by MCR have been investigated using hybrid density functional theory with recent developments, in particular including dispersion effects. An active-site model was constructed based on the X-ray crystal structure. The calculations indicate that the MCR reaction is indeed reversible and proceeds via a methyl radical and a Ni-S(CoM) intermediate with reasonable reaction barriers in both directions. In a competing mechanism, the formation of the crucial Ni-methyl intermediate, was found to be strongly endergonic by over 20?kcal mol(-1) (including a barrier) with dispersion and entropy effects considered, and thus would not be reachable in a reasonable time under natural conditions.     

Chalcone JAI‐51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors

Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre‐wide synchrotron‐generated X‐ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI‐51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS‐bearing rats received either MRT, JAI‐51 or both treatments. JAI‐51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ～20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI‐51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI‐51 treatment alone had no effect on rat survival. MRT alone or associated with JAI‐51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI‐51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI‐51 increases the survival of 9LGS‐bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.     

Mechanism for catechol ring cleavage by non-heme iron intradiol dioxygenases: a hybrid DFT study

The mechanism of the catalytic reaction of protocatechuate 3,4-dioxygenase (3,4-PCD), a representative intradiol dioxygenase, was studied with the hybrid density functional method B3LYP. First, a smaller model involving only the iron first-shell ligands (His460, His462, and Tyr408) and the substrates (catechol and dioxygen) was used to probe various a priori plausible reaction mechanisms. Then, an extended model involving also the most important second-shell groups (Arg457, Gln477, and Tyr479) was used for the refinement of the preselected mechanisms. The computational results suggest that the chemical reactions constituting the catalytic cycle of intradiol dioxygenases involve: (1) binding of the substrate as a dianion, in agreement with experimental suggestions, (2) binding of dioxygen to the metal aided by an electron transfer from the substrate to O(2), (3) formation of a bridging peroxo intermediate and its conformational change, which opens the coordination site trans to His462, (4) binding of a neutral XOH ligand (H(2)O or Tyr447) at the open site, (5) proton transfer from XOH to the neighboring peroxo ligand yielding the hydroperoxo intermediate, (6) a Criegee rearrangement leading to the anhydride intermediate, and (7) hydrolysis of the anhydride to the final acyclic product. One of the most important results obtained is that the Criegee mechanism requires an in-plane orientation of the four atoms (two oxygen and two carbon atoms) mainly involved in the reaction. This orientation yields a good overlap between the two sigma orbitals involved, C-C sigma and O-O sigma, allowing an efficient electron flow between them. Another interesting result is that under some conditions, a homolytic O-O bond cleavage might compete with the Criegee rearrangement. The role of the second-shell residues and the substituent effects are also discussed.     

Epimerization and desaturation by carbapenem synthase (CarC). A hybrid DFT study

The mechanism of the unusual epimerization and desaturation reactions catalyzed by carbapenem synthase was investigated using the hybrid density functional method B3LYP. Several different models have been used in the calculations to study five component reactions. Both protonated and deprotonated models for the substrate have been explored so that the effects of hydrogen bonds could be characterized. Besides the iron site, it is proposed that a some tyrosine residue, possibly Tyr67, is involved in the hydrogen abstraction step. The calculated energetics and barrier heights support this hypothesis, and are consistent with the known experimental data concerning CarC and other 2-oxoglutarate dependent dioxygenases.     

The effect of backbone constraints: the case of water oxidation by the oxygen-evolving complex in PSII

The procedure for fixing atoms of amino acid residues in cluster model calculations on enzymes is reviewed. Examples from recent calculations on photosystem II (PSII) and Mo,Cu-dependent CO dehydrogenase are given. In this context, the cluster model work on finding a mechanism for O-O bond formation and a structure of the oxygen-evolving complex in PSII is also reviewed. In that work, fixing certain atoms played an important role. The main part of the present study concerns the mechanism in PSII using models based on the new high-resolution (1.9 ?) X-ray structure, which is compared to that using the old, theoretically suggested, structure. It is concluded that the mechanism remains the same, with a similar barrier height. Finally, a connection between the OEC structure and Mn,Ca-containing minerals is also briefly discussed.     

Mapping the frontier electronic structures of triphenylamine based organic dyes at TiO2 interfaces

The frontier electronic structures of a series of organic dye molecules containing a triphenylamine moiety, a thiophene moiety and a cyanoacrylic acid moiety have been investigated by photoelectron spectroscopy (PES), X-ray absorption spectroscopy (XAS), X-ray emission spectroscopy (XES) and resonant photoelectron spectroscopy (RPES). The experimental results were compared to electronic structure calculations on the molecules, which are used to confirm and enrich the assignment of the spectra. The approach allows us to experimentally measure and interpret the basic valence energy level structure in the dye, including the highest occupied energy level and how it depends on the interaction between the different units. Based on N 1s X-ray absorption and emission spectra we also obtain insight into the structure of the excited states, the molecular orbital composition and dynamics. Together the results provide an experimentally determined energy level map useful in the design of these types of materials. Included are also results indicating femtosecond charge redistribution at the dye/TiO(2) interface.     

Theoretical insights into heme-catalyzed oxidation of cyclohexane to adipic acid

Adipic acid is a key compound in the chemical industry, where it is mainly used in the production of polymers. The conventional process of its generation requires vast amounts of energy and, moreover, produces environmentally deleterious substances. Thus, there is interest in alternative ways to gain adequate amounts of adipic acid. Experimental reports on a one-pot iron-catalyzed conversion of cyclohexane to adipic acid motivated a theoretical investigation based on density functional theory calculations. The process investigated is interesting because it requires less energy than contemporary methods and does not produce environmentally harmful side products. The aim of the present contribution is to gain insight into the mechanism of the iron-catalyzed cyclohexane conversion to provide a basis for the further development of this process. The rate-limiting step of the process is discussed, but considering the accuracy of the calculations, it is difficult to ensure whether the rate-limiting step is in the substrate oxidation or in the generation of the catalytically active species. It is shown that the slowest step in the substrate oxidation is the conversion of cyclohexanol to cyclohexane-1,2-diol. Hydrogen-atom transfer from one of the OH groups of cyclohexane-1,2-diol makes the intradiol cleavage occur spontaneously.     

O-O bond formation in the S(4) state of the oxygen-evolving complex in photosystem II

Based on recent X-ray structures of the oxygen-evolving complex in photosystem II, quantum chemical geometry optimizations of several thousand structures have been performed in order to elucidate the mechanism for dioxygen formation. Many of the results of these calculations have been presented previously. The energetically most stable structure of the S(4) state has been used in the present study to investigate essentially all the possible ways the O--O bond can be formed in this structure. A key feature, emphasized previously, of the S(4) state is that an oxygen radical ligand is present rather than an Mn(V) state. Previous studies have indicated that this oxygen radical can form an O--O bond by an attack from a water molecule in the second coordination shell. The present systematic investigation has led to a new type of mechanism that is significantly favored over the previous one. A calculated transition-state barrier of 12.5 kcal mol(-1) was found for this mechanism, whereas the best previous results gave 18-20 kcal mol(-1). A requirement on the spin alignment for a low barrier is formulated.