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  • 1.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Borowski, Tomasz
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Oxygen Activation by Rieske Non-Heme Iron Oxygenases, a Theoretical Insight2004In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 108, no 34, p. 13031-13041Article in journal (Refereed)
    Abstract [en]

    The first steps of dioxygen activation in naphthalene 1,2-dioxygenase have been investigated by means of hybrid density functional theory. Reduction of molecular oxygen by this Rieske dioxygenase occurs in the catalytic domain accommodating a mononuclear non-heme iron(II) complex, and it requires two external electrons ultimately delivered by a Rieske [2Fe−2S] cluster hosted in the neighboring domain. Theoretical tools have been applied to gain insight into the O2-binding step and into the first one-electron-transfer process involving the mononuclear and the Rieske centers, and yielding an iron(II)−superoxo intermediate. The reaction, which is mimicked with a model including both metal sites, is found to be a reversible equilibrium. Although the entropic loss associated with the binding of O2 to iron(II) is not canceled by the corresponding enthalpic binding energy, it is, however, balanced by the exothermicity of the electron transfer process from the Rieske cluster to the dioxygen-bound iron(II) complex. The rationalization for the calculated energetics is related to the values of the ionization potential (IP) of the Rieske cluster and the electron affinity (EA) of the mononuclear iron complex: the latter is computed to be higher than the former, when dioxygen is bound to the metal. The possibility that a second external electron is delivered to the mononuclear site before dioxygenation of the substrate has also been examined. It is shown that, if the second electron is available in the Rieske domain, the electron transfer process is energetically favored. The results acquired with the large model comprising the two metal centers are compared to the corresponding information collected from the study of smaller models, where either the mononuclear iron complex or the Rieske cluster is included.

  • 2.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    A Theoretical Study of the Cis-Dihydroxylation Mechanism in Naphthalene 1,2-dioxygenase2004In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 9, no 4, p. 439-452Article in journal (Refereed)
    Abstract [en]

    The catalytic mechanism of naphthalene 1,2-dioxygenase has been investigated by means of hybrid density functional theory. This Rieske-type enzyme, which contains an active site hosting a mononuclear non-heme iron(II) complex, uses dioxygen and two electrons provided by NADH to carry out the cis-dihydroxylation of naphthalene. Since a (hydro)peroxo-iron(III) moiety has been proposed to be involved in the catalytic cycle, it was probed whether and how this species is capable of cis-dihydroxylation of the aromatic substrate. Different oxidation and protonation states of the Fe–O2 complex were studied on the basis of the crystal structure of the enzyme with oxygen bound side-on to iron. It was found that feasible reaction pathways require a protonated peroxo ligand, FeIII–OOH; the deprotonated species, the peroxo-iron(III) complex, was found to be inert toward naphthalene. Among the different chemical patterns which have been explored, the most accessible one involves an epoxide intermediate, which may subsequently evolve toward an arene cation, and finally to the cis-diol. The possibility that an iron(V)-oxo species is formed prior to substrate hydroxylation was also examined, but found to implicate a rather high energy barrier. In contrast, a reasonably low barrier might lead to a high-valent iron-oxo species [i.e. iron(IV)-oxo] if a second external electron is supplied to the mononuclear iron center before dioxygenation.

  • 3.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Mechanism of Aromatic Hydroxylation by an Activated Fe(IV)=O Core in Tetrahydrobiopterin-Dependent Hydroxylases2003In: Chemistry: a European Journal, ISSN 0947-6539, Vol. 9, no 17, p. 4055-4067Article in journal (Refereed)
  • 4.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin-Dependent Amino Acid Hydroxylases2003In: Chemistry: a European Journal, ISSN 0947-6539, Vol. 9, no 1, p. 106-115Article in journal (Refereed)
  • 5.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Que, Jr, Lawrence
    A Density Functional Study of a Biomimetic Non-Heme Iron Catalyst: Insights into Alkane Hydroxylation and Olefin Oxidation by a Formally HO-Fe(V)=O Oxidant2004In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 11, no 2, p. 692-705Article in journal (Refereed)
    Abstract [en]

    The reactivity of [HO(tpa)FeVO] (TPA=tris(2-pyridylmethyl)amine), derived from OO bond heterolysis of its [H2O(tpa)FeIIIOOH] precursor, was explored by means of hybrid density functional theory. The mechanism for alkane hydroxylation by the high-valent iron–oxo species invoked as an intermediate in Fe(tpa)/H2O2 catalysis was investigated. Hydroxylation of methane and propane by HOFeVO was studied by following the rebound mechanism associated with the heme center of cytochrome P450, and it is demonstrated that this species is capable of stereospecific alkane hydroxylation. The mechanism proposed for alkane hydroxylation by HOFeVO accounts for the experimentally observed incorporation of solvent water into the products. An investigation of the possible hydroxylation of acetonitrile (i.e., the solvent used in the experiments) shows that the activation energy for hydrogen-atom abstraction by HOFeVO is rather high and, in fact, rather similar to that of methane, despite the similarity of the HCH2CN bond strength to that of the secondary CH bond in propane. This result indicates that the kinetics of hydrogen-atom abstraction are strongly affected by the cyano group and rationalizes the lack of experimental evidence for solvent hydroxylation in competition with that of substrates such as cyclohexane.

  • 6.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Que, Jr., Lawrence
    A Density Functional Study of O-O Bond Cleavage for a Biomimetic Non-Heme Iron Complex Demonstrating an Fe(V)-Intermediate2002In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, no 37, p. 11056-11063Article in journal (Refereed)
  • 7.
    Bassan, Arianna
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Que, Jr., Lawrence
    Theoretical Studies on Olefin Oxidation by Biomimetic Non-Heme Iron(III)-Hydroperoxo ComplexesManuscript (Other academic)
  • 8.
    Blomberg, L. Mattias
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Reduction of Nitric Oxide in Bacterial Nitric Oxide Reductase: A Theoretical Model Study2006In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1757, no 4, p. 240-252Article in journal (Refereed)
    Abstract [en]

    The mechanism of the nitric oxide reduction in a bacterial nitric oxide reductase (NOR) has been investigated in two model systems of the heme-b3-FeB active site using density functional theory (B3LYP). A model with an octahedral coordination of the non-heme FeB consisting of three histidines, one glutamate and one water molecule gave an energetically feasible reaction mechanism. A tetrahedral coordination of the non-heme iron, corresponding to the one of CuB in cytochrome oxidase, gave several very high barriers which makes this type of coordination unlikely. The first nitric oxide coordinates to heme b3 and is partly reduced to a more nitroxyl anion character, which activates it toward an attack from the second NO. The product in this reaction step is a hyponitrite dianion coordinating in between the two irons. Cleaving an NO bond in this intermediate forms an FeB (IV)O and nitrous oxide, and this is the rate determining step in the reaction mechanism. In the model with an octahedral coordination of FeB the intrinsic barrier of this step is 16.3 kcal/mol, which is in good agreement with the experimental value of 15.9 kcal/mol. However, the total barrier is 21.3 kcal/mol, mainly due to the endergonic reduction of heme b3 taken from experimental reduction potentials. After nitrous oxide has left the active site the ferrylic FeB will form a μ-oxo bridge to heme b3 in a reaction step exergonic by 45.3 kcal/mol. The formation of a quite stable μ-oxo bridge between heme b3 and FeB is in agreement with this intermediate being the experimentally observed resting state in oxidized NOR. The formation of a ferrylic non-heme FeB in the proposed reaction mechanism could be one reason for having an iron as the non-heme metal ion in NOR instead of a Cu as in cytochrome oxidase.

  • 9.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Can Reduction of NO to N2O in Cytochrome c Dependent Nitric Oxide Reductase Proceed through a Trans-Mechanism?2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 1, p. 120-131Article in journal (Refereed)
    Abstract [en]

    As part of microbial denitrification, NO is reduced to N2O in the membrane bound enzyme nitric oxide reductase, NOR The N N coupling occurs in the diiron binuclear active site, BNC, and different mechanisms for this reaction step have been suggested. Computational studies have supported a so-called cis:b(3)-mechanism, in which the hyponitrite product of the reductive N N bond formation coordinates with one nitrogen to the heme iron and with both oxygens to the non-heme iron in the BNC. In contrast, experimental results have been interpreted to support a so-called trans-mechanism, in which the hyponitrite intermediate coordinates with one nitrogen atom to each of the two iron ions. Hybrid density functional theory is used here to perform an extensive search for possible intermediates of the NO reduction in the cNOR enzyme. It is found that hyponitrite structures coordinating with their negatively charged oxygens to the positively charged iron ions are the most stable ones. The hyponitrite intermediate involved in the suggested trans-mechanism, which only coordinates with the nitrogens to the iron ions, is found to be prohibitively high in energy, leading to a too slow reaction, which should rule out this mechanism. Furthermore, intermediates binding one NO molecule to each iron ion in the BNC, which have been suggested to initiate the trans-mechanism, are found to be too high in energy to be observable, indicating that the experimentally observed electron paramagnetic resonance signals, taken to support such an iron-nitrosyl dimer intermediate, should be reinterpreted.

  • 10.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    How Quantum Chemistry Can Solve Fundamental Problems in Bioenergetics2015In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 115, no 18, p. 1197-1201Article in journal (Refereed)
    Abstract [en]

    Three different enzymes are discussed, cytochrome c oxidase, involved in aerobic respiration, cytochrome c dependent nitric oxide reductase, involved in denitrification (anaerobic respiration), and photosystem II, involved in photosynthesis. For all three systems, free energy profiles for the entire catalytic cycle are obtained from quantum mechanical calculations on large cluster models of the active sites, using hybrid density functional theory with the B3LYP* functional. The free energy pro-files are used to solve different fundamental problems concerning energy conservation, enzymatic reaction mechanisms and structure, and also to explain experimental results that seem to be in conflict with each other. Possible future applications to related problems using similar methodology are suggested.

  • 11.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mechanism of Oxygen Reduction in Cytochrome c Oxidase and the Role of the Active Site Tyrosine2016In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 3, p. 489-500Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase, the terminal enzyme in the respiratory chain, reduces molecular oxygen to water and stores the released energy through electrogenic chemistry and proton pumping across the membrane. Apart from the heme-copper binuclear center, there is a conserved tyrosine residue in the active site (BNC). The tyrosine delivers both an electron and a proton during the O-O bond cleavage step, forming a tyrosyl radical. The catalytic cycle then occurs in four reduction steps, each taking up one proton for the chemistry (water formation) and one proton to be pumped. It is here suggested that in three of the reduction steps the chemical proton enters the center of the BNC, leaving the tyrosine unprotonated with radical character. The reproprotonation of the tyrosine occurs first in the final reduction step before binding the next oxygen molecule. It is also suggested that this reduction mechanism and the presence of the tyrosine are essential for the proton pumping. Density functional theory calculations on large cluster models of the active site show that only the intermediates with the proton in the center of the BNC and with an unprotonated tyrosyl radical have a high electron affinity of similar size as the electron donor, which is essential for the ability to take up two protons per electron and thus for the proton pumping. This type of reduction mechanism is also the only one that gives a free energy profile in accordance with experimental observations for the amount of proton pumping in the working enzyme.

  • 12.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Borowski, Tomasz
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Liao, Rong-Zhen
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Quantum Chemical Studies of Mechanisms for Metalloenzymes2014In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 114, no 7, p. 3601-3658Article, review/survey (Refereed)
  • 13.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    A quantum chemical study of the mechanism for proton-coupled electron transfer leading to proton pumping in cytochrome c oxidase2010In: Molecular Physics, ISSN 0026-8976, E-ISSN 1362-3028, Vol. 108, no 19-20, p. 2733-2743Article in journal (Refereed)
    Abstract [en]

    The proton pumping mechanism in cytochrome c oxidase, the terminal enzyme in the respiratory chain, has been investigated using hybrid DFT with large chemical models. In previous studies, a gating mechanism was suggested based on electrostatic interpretations of kinetic experiments. The predictions from that analysis are tested here. The main result is that the suggestion of a positively charged transition state for proton transfer is confirmed, while some other suggestions for the gating are not supported. It is shown that a few critical relative energy values from the earlier studies are reproduced with quite high accuracy using the present model calculations. Examples are the forward barrier for proton transfer from the N-side of the membrane to the pump-loading site when the heme a cofactor is reduced, and the corresponding back leakage barrier when heme a is oxidised. An interesting new finding is an unexpected double-well potential for proton transfer from the N-side to the pump-loading site. In the intermediate between the two transition states found, the proton is bound to PropD on heme a. A possible purpose of this type of potential surface is suggested here. The accuracy of the present values are discussed in terms of their sensitivity to the choice of dielectric constant. Only one energy value, which is not critical for the present mechanism, varies significantly with this choice and is therefore less certain.

  • 14.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient2015In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, no 3, p. 364-376Article in journal (Refereed)
    Abstract [en]

    Experiments have shown that the A-family cytochrome c oxidases pump four protons per oxygen molecule, also at a high electrochemical gradient. This has been considered a puzzle, since two of the reduction potentials involved, Cu(II) and Fe(III), were estimated from experiments to be too low to afford proton pumping at a high gradient The present quantum mechanical study (using hybrid density functional theory) suggests a solution to this puzzle. First, the calculations show that the charge compensated Cu(II) potential for Cu-B is actually much higher than estimated from experiment, of the same order as the reduction potentials for the tyrosyl radical and the ferryl group, which are also involved in the catalytic cycle. The reason for the discrepancy between theory and experiment is the very large uncertainty in the experimental observations used to estimate the equilibrium potentials, mainly caused by the lack of methods for direct determination of reduced Cu-B. Second, the calculations show that a high energy metastable state, labeled E-H, is involved during catalytic turnover. The E-H state mixes the low reduction potential of Fe(III) in heme a(3) with another, higher potential, here suggested to be that of the tyrosyl radical, resulting in enough exergonicity to allow proton pumping at a high gradient In contrast, the corresponding metastable oxidized state, O-H, is not significantly higher in energy than the resting state, O. Finally, to secure the involvement of the high energy E-H state it is suggested that only one proton is taken up via the K-channel during catalytic turnover.

  • 15.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Improved free energy profile for reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR)2016In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 37, no 19, p. 1810-1818Article in journal (Refereed)
    Abstract [en]

    Quantum chemical calculations play an essential role in the elucidation of reaction mechanisms for redox-active metalloenzymes. For example, the cleavage and the formation of covalent bonds can usually not be described only on the basis of experimental information, but can be followed by the calculations. Conversely, there are properties, like reduction potentials, which cannot be accurately calculated. Therefore, computational and experimental data has to be carefully combined to obtain reliable descriptions of entire catalytic cycles involving electron and proton uptake from donors outside the enzyme. Such a procedure is illustrated here, for the reduction of nitric oxide (NO) to nitrous oxide and water in the membrane enzyme, cytochrome c dependent nitric oxide reductase (cNOR). A surprising experimental observation is that this reaction is nonelectrogenic, which means that no energy is conserved. On the basis of hybrid density functional calculations a free energy profile for the entire catalytic cycle is obtained, which agrees much better with experimental information on the active site reduction potentials than previous ones. Most importantly the energy profile shows that the reduction steps are endergonic and that the entire process is rate-limited by high proton uptake barriers during the reduction steps. This result implies that, if the reaction were electrogenic, it would become too slow when the gradient is present across the membrane. This explains why this enzyme does not conserve any of the free energy released.

  • 16.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Mechanism for N2O Generation in Bacterial Nitric Oxide Reductase: A Quantum Chemical Study2012In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 51, no 25, p. 5173-5186Article in journal (Refereed)
    Abstract [en]

    The catalytic mechanism of reduction of NO to N2O in the bacterial enzyme nitric oxide reductase has been investigated using hybrid density functional theory and a model of the binuclear center (BNC) based on the newly determined crystal structure. The calculations strongly suggest a so-called cis:b(3) mechanism, while the commonly suggested trans mechanism is found to be energetically unfavorable. The mechanism suggested here involves a stable cis-hyponitrite, and it is shown that from this intermediate one N-O bond can be cleaved without the transfer of a proton or an electron into the binuclear active site, in agreement with experimental observations. The fully oxidized intermediate in the catalytic cycle and the resting form of the enzyme are suggested to have an oxo-bridged BNC with two high-spin ferric irons antiferromagnetically coupled. Both steps of reduction of the BNC after N2O formation are found to be pH-dependent, also in agreement with experiment. Finally, it is found that the oxo bridge in the oxidized BNC can react with NO to give nitrite, which explains the experimental observations that the fully oxidized enzyme reacts with NO, and most likely also the observed substrate inhibition at higher NO concentrations.

  • 17.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Proton pumping in cytochrome c oxidase: Energetic requirements and the role of two proton channels2014In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1837, no 7, p. 1165-1177Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase is a superfamily of membrane bound enzymes catalyzing the exergonic reduction of molecular oxygen to water, producing an electrochemical gradient across the membrane. The gradient is formed both by the electrogenic chemistry, taking electrons and protons from opposite sides of the membrane, and by proton pumping across the entire membrane. In the most efficient subfamily, the A-family of oxidases, one proton is pumped in each reduction step, which is surprising considering the fact that two of the reduction steps most likely are only weakly exergonic. Based on a combination of quantum chemical calculations and experimental information, it is here shown that from both a thermodynamic and a kinetic point of view, it should be possible to pump one proton per electron also with such an uneven distribution of the free energy release over the reduction steps, at least up to half the maximum gradient. A previously suggested pumping mechanism is developed further to suggest a reason for the use of two proton transfer channels in the A-family. Since the rate of proton transfer to the binuclear center through the D-channel is redox dependent, it might become too slow for the steps with low exergonicity. Therefore, a second channel, the K-channel, where the rate is redox-independent is needed. A redox-dependent leakage possibility is also suggested, which might be important for efficient energy conservation at a high gradient. A mechanism for the variation in proton pumping stoichiometry over the different subfamilies of cytochrome oxidase is also suggested. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

  • 18.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Protonation of the binuclear active site in cytochrome c oxidase decreases the reduction potential of Cu-B2015In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, no 10, p. 1173-1180Article in journal (Refereed)
    Abstract [en]

    One of the remaining mysteries regarding the respiratory enzyme cytochrome c oxidase is how proton pumping can occur in all reduction steps in spite of the low reduction potentials observed in equilibrium titration experiments for two of the active site cofactors, CUB(II) and Fe-a3(III). It has been speculated that, at least the copper cofactor can acquire two different states, one metastable activated state occurring during enzyme turnover, and one relaxed state with lower energy, reached only when the supply of electrons stops. The activated state should have a transiently increased Cu-B(II) reduction potential, allowing proton pumping. The relaxed state should have a lower reduction potential, as measured in the titration experiments. However, the structures of these two states are not known. Quantum mechanical calculations show that the proton coupled reduction potential for Cu-B is inherently high in the active site as it appears after reaction with oxygen, which explains the observed proton pumping. It is suggested here that, when the flow of electrons ceases, a relaxed resting state is formed by the uptake of one extra proton, on top of the charge compensating protons delivered in each reduction step. The extra proton in the active site decreases the proton coupled reduction potential for Cu-B by almost half a volt, leading to agreement with titration experiments. Furthermore, the structure for the resting state with an extra proton is found to have a hydroxo-bridge between Cu-B(II) and Fe-a3(III), yielding a magnetic coupling that can explain the experimentally observed EPR silence.

  • 19.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantum chemistry as a tool in bioenergetics2010In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1797, no 2, p. 129-142Article, review/survey (Refereed)
    Abstract [en]

    Recent developments of quantum chemical methods have made it possible to tackle crucial questions in bioenergetics. The most important systems, cytochrome c oxidase in cellular respiration and photosystem II (PSII) in photosynthesis will here be used as examples to illustrate the power of the quantum chemical tools. One main contribution from quantum chemistry is to put mechanistic suggestions onto an energy scale. Accordingly, free energy profiles can be constructed both for reduction of molecular oxygen in cytochrome c oxidase and water oxidation in PSII, including O-O bond cleavage and formation, and also proton pumping in cytochrome c oxidase. For the construction of the energy diagrams, the computational results sometimes have to be combined with experimental information, such as reduction potentials and rate constants for individual steps in the reactions.

  • 20.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    The mechanism for proton pumping in cytochrome c oxidase from an electrostatic and quantum chemical perspective2012In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1817, no 4, p. 495-505Article, review/survey (Refereed)
    Abstract [en]

    The mechanism for proton pumping in cytochrome c oxidase in the respiratory chain, has for decades been one of the main unsolved problems in biochemistry. However, even though several different suggested mechanisms exist, many of the steps in these mechanisms are quite similar and constitute a general consensus framework for discussing proton pumping. When these steps are analyzed, at least three critical gating situations are found, and these points are where the suggested mechanisms in general differ. The requirements for gating are reviewed and analyzed in detail, and a mechanism is suggested, where solutions for all the gating situations are formulated. This mechanism is based on an electrostatic analysis of a kinetic experiment for the O to E transition. The key component of the mechanism is a positively charged transition state. An electron on heme a opens the gate for proton transfer from the N-side to a pump loading site (PLS). When the negative charge of the electron is compensated by a chemical proton, the positive transition state prevents backflow from the PLS to the N-side at the most critical stage of the pumping process. The mechanism has now been tested by large model DFT calculations, and these calculations give strong support for the suggested mechanism. This article is part of a Special Issue entitled: Respiratory Oxidases.

  • 21.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Why is the reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR) not electrogenic?2013In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1827, no 7, p. 826-833Article in journal (Refereed)
    Abstract [en]

    The membrane-bound enzyme cNOR (cytochrome c dependent nitric oxide reductase) catalyzes the reduction of NO in a non-electrogenic process. This is in contrast to the reduction of O-2 in cytochrome c oxidase (CcO), the other member of the heme-copper oxidase family, which stores energy by the generation of a membrane gradient. This difference between the two enzymes has not been understood, but it has been speculated to be of kinetic origin, since per electron the NO reduction is more exergonic than the O-2 reduction, and the energy should thus be enough for an electrogenic process. However, it has not been clear how and why electrogenicity, which mainly affects the thermodynamics, would slow down the very exergonic NO reduction. Quantum chemical calculations are used to construct a free energy profile for the catalytic reduction of NO in the active site of cNOR. The energy profile shows that the reduction of the NO molecules by the enzyme and the formation of N2O are very exergonic steps, making the rereduction of the enzyme endergonic and rate-limiting for the entire catalytic cycle. Therefore the NO reduction cannot be electrogenic, i.e. cannot take electrons and protons from the opposite sides of the membrane, since it would increase the endergonicity of the rereduction when the gradient is present, thereby increasing the rate-limiting barrier, and the reaction would become too slow. It also means that proton pumping coupled to electron transfer is not possible in cNOR In CcO the corresponding rereduction of the enzyme is very exergonic.

  • 22.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The mechanism for oxygen reduction in cytochrome c dependent nitric oxide reductase (cNOR) as obtained from a combination of theoretical and experimental results2017In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1858, no 11, p. 884-894Article in journal (Refereed)
    Abstract [en]

    Bacterial NO-reductases (NOR) belong to the heme-copper oxidase (HCuO) superfamily, in which most members are O-2-reducing, proton-pumping enzymes. This study is one in a series aiming to elucidate the reaction mechanisms of the HCuOs, including the mechanisms for cellular energy conservation. One approach towards this goal is to compare the mechanisms for the different types of HCuOs, cytochrome c oxidase (CcO) and NOR, reducing the two substrates O-2 and NO. Specifically in this study, we describe the mechanism for oxygen reduction in cytochrome c dependent NOR (cNOR). Hybrid density functional calculations were performed on large cluster models of the cNOR binuclear active site. Our results are used, together with published experimental information, to construct a free energy profile for the entire catalytic cycle. Although the overall reaction is quite exergonic, we show that during the reduction of molecular oxygen in cNOR, two of the reduction steps are endergonic with high barriers for proton uptake, which is in contrast to oxygen reduction in CcO, where all reduction steps are exergonic. This difference between the two enzymes is suggested to be important for their differing capabilities for energy conservation. An additional result from this study is that at least three of the four reduction steps are initiated by proton transfer to the active site, which is in contrast to CcO, where electrons always arrive before the protons to the active site. The roles of the non-heme metal ion and the redox-active tyrosine in the active site are also discussed.

  • 23. Borowski, Tomasz
    et al.
    Wojcik, Anna
    Milaczewska, Anna
    Georgiev, Valentin
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Faculty of Science, Department of Physics.
    The alkenyl migration mechanism catalyzed by extradiol dioxygenases: a hybrid dft study2012In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 17, no 6, p. 881-890Article in journal (Refereed)
    Abstract [en]

    6-Hydroxymethyl-6-methylcyclohexa-2,4-dienone is a mechanistic probe which when incubated with an extradiol dioxygenase yields a 2-tropolone product. This observation was originally interpreted as evidence supporting a direct heterolytic 1,2-alkenyl migration mechanism for a ring expansion reaction catalyzed by this class of Fe(II)-dependent nonheme enzymes (Xin and Bugg in J Am Chem Soc 130:10422-10430, 2008). In the work reported in this contribution we used quantum chemical methods to test whether such a mechanism is energetically possible and we found that it is not, neither for the mechanistic probe nor for the native catalytic cycle intermediate. Models of increasing complexity were used to calculate energy barriers to the heterolytic 1,2-alkenyl migration and alternative radical mechanisms. It was found that the former involves substantially higher barriers than the latter. A tentative radical mechanism that accounts for the transformation of the probe substrate to 2-tropolone was also proposed, and it involves acceptable barriers.

  • 24. Chen, Shi-Lu
    et al.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    An investigation of possible competing mechanisms for Ni-containing methyl-coenzyme M reductase2014In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 16, no 27, p. 14029-14035Article in journal (Refereed)
    Abstract [en]

    Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation from methyl-coenzyme M (CH3-SCoM) and coenzyme B (CoB-SH), and also its reverse reaction (methane oxidation). Based on extensive experimental and theoretical investigations, it has turned out that a mechanism including an organometallic methyl-Ni(III)F-430 intermediate is inaccessible, while another mechanism involving a methyl radical and a Ni(II)-SCoM species currently appears to be the most acceptable one for MCR. In the present paper, using hybrid density functional theory and an active-site model based on the X-ray crystal structure, two other mechanisms were studied and finally also ruled out. One of them, involving proton binding on the CH3-SCoM substrate, which should facilitate methyl-Ni(III)F-430 formation, is demonstrated to be quite unfavorable since the substrate has a much smaller proton affinity than the F-430 cofactor. Another one (oxidative addition mechanism) is also shown to be unfavorable for the MCR reaction, due to the large endothermicity for the formation of the ternary intermediate with side-on C-S (for CH3-SCoM) or C-H (for methane) coordination to Ni.

  • 25.
    Chen, Shi-Lu
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    How Is a Co-Methyl Intermediate Formed in the Reaction of Cobalamin-Dependent Methionine Synthase?: Theoretical Evidence for a Two-Step Methyl Cation Transfer Mechanism2011In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, no 14, p. 4066-4077Article in journal (Refereed)
    Abstract [en]

    A methyl-Co(cobalamin) species has been characterized to be a crucial intermediate in the last step of the de novo biosynthesis of methionine catalyzed by cobalamin-dependent methionine synthase (MetH). However, exactly how it is formed is still an open question. In the present article, the formation of the methyl-Co(cobalamin) species in MetH has been investigated with B3LYP* hybrid DFT including van der Waals (vdW) interactions (i.e., dispersion) and using a chemical model built on X-ray crystal structures. The methyl cation and radical transfer mechanisms have been examined in various protonation states. The calculations reveal that the CH(3)-Co(III)(cobalamin) formation in MetH proceeds along a stepwise pathway, where the first step is a methyl cation transfer from the protonated methyltetrahydrofolate (CH(3)-THF) substrate to the Co(I)cobalamin. The second step is a binding of His759 to the other side (a-face) of Co. The former methyl transfer is computed to be the rate-limiting step with a barrier of 18 kcal/mol, which is reduced to 13 kcal/mol when dispersion is included. For the first step, the protonation at the methyl-bound nitrogen of CH(3)-THF is very important. The methyl transfer is otherwise unreachable with a very high barrier of similar to 38 kcal/mol. The deprotonation of the alpha-face His759-Asp757-Ser810 triad is found to be much less significant but slightly facilitates the CH(3)-Co(III)Cbl formation. There has been a long-standing discrepancy of 10-20 kcal/mol between theory and experiment in previous B3LYP computations of the Co C bond dissociation energy for the methyl-Co(cobalamin) species. The calculations indicate that the lack of dispersion (similar to 11 kcal/mol) is the main origin of this puzzling problem. With these effects, B3LYP* gives a bond strength of 32 kcal/mol compared to the experimental value of 37 +/- 3 kcal/mol. Overall, the present calculations give many examples of dispersion that makes non-negligible contributions to the energetics of enzyme reactions, especially for systems involving at least one large reacting fragment approaching or departing.

  • 26. Chen, Shi-Lu
    et al.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    How Is Methane Formed and Oxidized Reversibly When Catalyzed by Ni-Containing Methyl-Coenzyme M Reductase?2012In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 20, p. 6309-6315Article in journal (Refereed)
    Abstract [en]

    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.

  • 27.
    Chen, Shi-Lu
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Pelmenschikov, Vladimir
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per .E.M.
    Stockholm University, Faculty of Science, Department of Physics.
    Is There a Ni-Methyl Intermediate in the Mechanism of Methyl-Coenzyme M Reductase (MCR)?2009In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, p. 9912-9913Article in journal (Refereed)
  • 28.
    Georgiev, Valentin
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Borowski, Tomasz
    Polish Academy of Sciences.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    A comparison of the reaction mechanisms of iron- and manganese-containing 2,3-HPCD: an important spin transition for manganese2008In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 13, no 6, p. 929-40Article in journal (Refereed)
    Abstract [en]

    Homoprotocatechuate (HPCA) dioxygenases are enzymes that take part in the catabolism of aromatic compounds in the environment. They use molecular oxygen to perform the ring cleavage of ortho-dihydroxylated aromatic compounds. A theoretical investigation of the catalytic cycle for HPCA 2,3-dioxygenase isolated from Brevibacterium fuscum (Bf 2,3-HPCD) was performed using hybrid DFT with the B3LYP functional, and a reaction mechanism is suggested. Models of different sizes were built from the crystal structure of the enzyme and were used in the search for intermediates and transition states. It was found that the enzyme follows a reaction pathway similar to that for other non-heme iron dioxygenases, and for the manganese-dependent analog MndD, although with different energetics. The computational results suggest that the rate-limiting step for the whole reaction of Bf 2,3-HPCD is the protonation of the activated oxygen, with an energy barrier of 17.4 kcal/mol, in good agreement with the experimental value of 16 kcal/mol obtained from the overall rate of the reaction. Surprisingly, a very low barrier was found for the O-O bond cleavage step, 11.3 kcal/mol, as compared to 21.8 kcal/mol for MndD (sextet spin state). This result motivated additional studies of the manganese-dependent enzyme. Different spin coupling between the unpaired electrons on the metal and on the evolving substrate radical was observed for the two enzymes, and therefore the quartet spin state potential energy surface of the MndD reaction was studied. The calculations show a crossing between the sextet and the quartet surfaces, and it was concluded that a spin transition occurs and determines a barrier of 14.4 kcal/mol for the O-O bond cleavage, which is found to be the rate-limiting step in MndD. Thus the two 83% identical enzymes, using different metal ions as co-factors, were found to have similar activation energies (in agreement with experiment), but different rate-limiting steps.

  • 29.
    Georgiev, Valentin
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Noack, Holger
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    Stockholm University, Faculty of Science, Department of Physics.
    A DFT Study on the Catalytic Reactivity of a Functional Model Complex for  Intradiol-Cleaving Dioxygenases2010In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 17, p. 5878-5885Article in journal (Refereed)
    Abstract [en]

    The enzymatic ring cleavage of catechol derivatives is catalyzed by two groups of dioxygenases: extradiol- and intradiol-cleaving dioxygenases. Although having different oxidation state of their nonheme iron sites and different ligand coordinations, both groups of enzymes involve a common peroxy intermediate in their catalytic cycles. The factors that lead to either extradiol cleavage resulting in 2-hydroxymuconaldehyde or intradiol cleavage resulting in muconic acid are not fully understood. Well-characterized model compounds that mimic the functionality of these enzymes offer a basis for direct comparison to theoretical results. In this study the mechanism of a biomimetic iron complex is investigated with density functional theory (DFT). This complex catalyzes the ring opening of catecholate with exclusive formation of the intradiol cleaved product. Several spin states are possible for the transition metal system, with the quartet state found to be of main importance during the reaction course. The mechanism investigated provides an explanation for the observed selectivity of the complex. First, a bridging peroxide is formed, which decomposes to an alkoxy radical by O−O homolysis. In contrast to the subsequent barrier-free intradiol C−C bond cleavage, the extradiol pathway proceeds via the formation of an epoxide, which requires an additional activation barrier.

  • 30.
    Johansson, Adam Johannes
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per. E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Quantifying the Effects of the Self-interaction Error in Density Functional Theory: When do the Delocalized States Appear? II. Iron-oxo Complexes and Closed-shell Substrate Molecules2008In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 129, p. 154301-Article in journal (Refereed)
    Abstract [en]

    Effects of the self-interaction error (SIE) in approximate density functional theory have several times been reported and quantified for the dissociation of charged radicals, charge transfer complexes, polarizabilities, and for transition states of reactions involving main-group molecules. In the present contribution, effects of the SIE in systems composed of a catalytic transition metal complex and a closed-shell substrate molecule are investigated. For this type of system, effects of the SIE have not been reported earlier. It is found that although the best density functionals (e.g., B3LYP) are capable of accurate predictions of structure, thermodynamics, and reactivity of such systems, there are situations and systems for which the magnitude of the SIE can be large, and for which the effects can be severe for the modeling of chemical reactivity. The largest energetic effect reported here is the artificial stabilization of a catalyst-substrate complex by as much as 18 kcal/mol. Also, the disappearance of significant energy barriers for hydrogen atom transfer in certain systems are reported. In line with earlier work, it is found that the magnitude of the SIE is related to the energetics of electron transfer between the metal catalyst and the substrate molecule. It is suggested that these problems might be circumvented by the inclusion of counterions or point charges that would alter the energetics of electron transfer. It is also pointed out that the effects of SIE in the modeling of transition metal reactivity need to be investigated further.

  • 31.
    Liu, Yan Fang
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Yu, Jian Guo
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Theoretical Study of the Oxidation of Phenolates by the [Cu2O2(N,N-di-tert-butylethylenediamine)2]2+Complex2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 6, p. 1942-1954Article in journal (Refereed)
    Abstract [en]

    Experiments have shown that the -2:2-peroxodicopper(II) complex [Cu2O2(N,N-di-tert-butylethylenediamine)2]2+ rapidly oxidizes 2,4-di-tert-butylphenolate into a mixture of catechol and quinone and that, at the extreme temperature of 120 degrees C, a bis--oxodicopper(III)phenolate intermediate, labeled complex A, can be observed. These experimental results suggest a new mechanism of action for the dinuclear copper-containing enzyme tyrosinase, involving an early OO bond-cleavage step. However, whether phenolate binding occurs before or after the cleavage of the OO bond has not been possible to answer. In this study, hybrid density functional theory is used to study the synthetic reaction and, based on the calculated free-energy profile, a mechanism is suggested for the entire phenolate-oxidation reaction that agrees with the experimental observations. Most importantly, the calculations show that the very first step in the reaction is the cleavage of the OO bond in the peroxo complex and that, subsequently, the phenolate substrate coordinates to one of the copper ions in the bis--oxodicopper(III) complex to yield the experimentally characterized phenolate intermediate (A). The oxidation of the phenolate substrate into a quinone then occurs in three steps: 1)CO bond formation, 2)coupled internal proton and electron transfer, and 3)electron transfer coupled to proton transfer from an external donor (acidic workup, experimentally). The first of these steps is rate limiting for the decay of complex A, with a calculated free-energy barrier of 10.7kcalmol1 and a deuterium kinetic isotope effect of 0.90, which are in good agreement with the experimental values of 11.2kcalmol1 and 0.83(+/- 0.09). The tert-butyl substituents on both the phenol substrate and the copper ligands need to be included in the calculations to give a correct description of the reaction mechanism.

  • 32.
    Noack, Holger
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Georgiev, Valentin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Johansson, Adam Johannes
    Theoretical Insights into Heme-Catalyzed Oxidation of Cyclohexane to Adipic Acid2011In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 50, no 4, p. 1194-1202Article in journal (Refereed)
    Abstract [en]

    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.

  • 33.
    Noack, Holger
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Georgiev, Valentin
    Stockholm University, Faculty of Science, Department of Physics.
    Johannson, Johannes Adam
    Department fur Chemie, Universität in Aachen.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E.M.
    Stockholm University, Faculty of Science, Department of Physics.
    The Conversion of Cyclohexane to Adipic Acid catalyzed by an Iron-Porphirin Complex. A theoretical studyManuscript (preprint) (Other academic)
  • 34.
    Noack, Holger
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Valentin, Georgiev
    Stockholm University, Faculty of Science, Department of Physics.
    Johansson, Adam Johannes
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E,M.
    Stockholm University, Faculty of Science, Department of Physics.
    Theoretical Insights into Heme Catalysed Oxidation of Cyclohexane to Adipic Acid Article in journal (Refereed)
    Abstract [en]

    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, pro- duces 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 DFT 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 further development of this process. The rate limiting step along the reaction path is discussed. Furthermore, it is shown that the C-C bond breaks spontaneously after an initial hydrogen atom abstraction from one of the cylohexane-1,2-diol hydroxides.

  • 35.
    Pelmenschikov, Vladimir
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R A
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E M
    Stockholm University, Faculty of Science, Department of Physics.
    Crabtree, Robert H
    A Mechanism from Quantum Chemical Studies for Methane Formation in Methanogenesis2002In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, no 15, p. 4039-4049Article in journal (Refereed)
    Abstract [en]

    The mechanism for methane formation in methyl-coenzyme M reductase (MCR) has been investigated using the B3LYP hybrid density functional method and chemical models consisting of 107 atoms. The experimental X-ray crystal structure of the enzyme in the inactive MCRox1-silent state was used to set up the initial model structure. The calculations suggest a mechanism not previously proposed, in which the most remarkable feature is the formation of an essentially free methyl radical at the transition state. The reaction cycle suggested starts from a Michaelis complex with CoB and methyl-CoM coenzymes bound and with a squareplanar coordination of the Ni(I) center in the tetrapyrrole F430 prosthetic group. In the rate-limiting step the methyl radical is released from methyl-CoM, induced by the attack of Ni(I) on the methyl-CoM thioether sulfur. In this step, the metal center is oxidized from Ni(I) to Ni(II). The resulting methyl radical is rapidly quenched by hydrogen-atom transfer from the CoB thiol group, yielding the methane molecule and the CoB radical. The estimated activation energy is around 20 kcal/mol, which includes a significant contribution from entropy due to the formation of the free methyl. The mechanism implies an inversion of configuration at the reactive carbon. The size of the inversion barrier is used to explain the fact that CF3−S−CoM is an inactive substrate. Heterodisulfide CoB−S−S−CoM formation is proposed in the final step in which nickel is reduced back to Ni(I). The suggested mechanism agrees well with experimental observations.

  • 36.
    Poiana, Federica
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    von Ballmoos, Christoph
    Gonska, Nathalie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Splitting of the O-O bond at the heme-copper catalytic site of respiratory oxidases2017In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 3, no 6, article id e1700279Article in journal (Refereed)
    Abstract [en]

    Heme-copper oxidases catalyze the four-electron reduction of O-2 to H2O at a catalytic site that is composed of a heme group, a copper ion (Cu-B), and a tyrosine residue. Results from earlier experimental studies have shown that the O-O bond is cleaved simultaneously with electron transfer from a low-spin heme (heme a/b), forming a ferryl state (P-R; Fe4+= O2-, Cu-B(2+)-OH-). We show that with the Thermus thermophilus ba(3) oxidase, at low temperature (10 degrees C, pH 7), electron transfer from the low-spin heme b to the catalytic site is faster by a factor of similar to 10 (tau congruent to 11 mu s) than the formation of the P-R ferryl (t. 110 ms), which indicates that O-2 is reduced before the splitting of the O-O bond. Application of density functional theory indicates that the electron acceptor at the catalytic site is a high-energy peroxy state [Fe3+-O--O-(H+)], which is formed before the P-R ferryl. The rates of heme b oxidation and P-R ferryl formation were more similar at pH 10, indicating that the formation of the high-energy peroxy state involves proton transfer within the catalytic site, consistent with theory. The combined experimental and theoretical data suggest a general mechanism for O-2 reduction by heme-copper oxidases.

  • 37.
    Roos, Katarina
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Physics.
    Formation of the Unusual Tyrosine-Valine Crosslink in the Manganese-Iron Heterodimer Oxidase from Mycobacterium tuberculosisManuscript (preprint) (Other academic)
  • 38.
    Rudbeck, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    The hydrolysis of E2P of Ca2+-ATPase: A theoretical studyManuscript (preprint) (Other academic)
  • 39.
    Rudbeck, Maria
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Infrared Spectrum of E2P of Ca2+-ATPaseManuscript (preprint) (Other academic)
  • 40.
    Rudbeck, Maria E.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hydrolysis of the E2P Phosphoenzyme of the Ca2+-ATPase: A Theoretical Study2013In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 31, p. 9224-9232Article in journal (Refereed)
    Abstract [en]

    Dephosphorylation of the E2P phosphoenzyme intermediate of the sarcoplasmic reticulum Ca2+-ATPase was studied using density functional theory. The hydrolysis reaction proceeds via a nucleophilic attack on the phosphorylated residue Asp351 by a water molecule, which is positioned by the nearby residue Glu183 acting as a base. The activation barrier was calculated to be 14.3 kcal/mol, which agrees well with values of 15-17 kcal/mol derived from experimentally observed rates. The optimized structure of the transition state reveals considerable bond breakage between phosphorus and the Asp351 oxygen (distance 2.19 angstrom) and little bond formation to the attacking water oxygen (distance 2.26 angstrom). Upon formation of the singly protonated phosphate product, Glu183 becomes protonated. The bridging aspartyl phosphate oxygen approaches Lys684 progressively when proceeding from the reactant state (distance 1.94 angstrom) via the transition state (1.78 angstrom) to the product state (1.58 angstrom). This stabilizes the negative charge that develops on the leaving group. The reaction was calculated to be slightly endergonic (+0.9 kcal/mol) and therefore reversible, in line with experimental findings. It is catalyzed by a preorganized active site with little movement of the nonreacting groups except for a rotation of Thr625 toward the phosphate group.

  • 41.
    Rudbeck, Maria E.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kumar, Saroj
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mroginski, Maria-Andrea
    Nilsson Lill, Sten O.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics.
    Barth, Andreas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Infrared Spectrum of Phosphoenol Pyruvate: Computational and Experimental Studies2009In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 12, p. 2935-2942Article in journal (Refereed)
    Abstract [en]

    The infrared spectrum of phosphoenol pyruvate (PEP) in aqueous solution was studied experimentally and theoretically in its fully ionized, singly protonated and doubly protonated form. The density functional theory with the B3LYP functional and with the 6-31G(d,p), 6-31++G(d,p), and 6-311++G(d,p) basis sets were used in the theoretical study. The calculations with the two latter basis sets and the CPCM continuum model for water showed good agreement with the experiments except for vibrations assigned to hydroxyl groups. These needed to be modeled with explicit water molecules. The effects of deuteration and of 13C2,3 labeling of PEP were reproduced by the calculations.

  • 42.
    Siegbahn, P.E.M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, M.R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    Bond-dissociation using hybrid DFT2010In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 110, p. 317-322Article in journal (Refereed)
    Abstract [en]

    The calculation of potential curves and potential surfaces is the main approach for quantum chemical studies of reaction mechanisms. For a sufficient accuracy, qualitatively correct descriptions of bond cleavages and bond formations are required. When large models are used, such as for systems of biological interest, in practice the only available method is DFT. The most common variant is hybrid DFT with the B3LYP functional. In the present study, two cases of bond dissociation using B3LYP are discussed, one for the single O–O bond in hydrogen peroxide, the other one for the hextuple bond in the chromium dimer. Quite accurate results are obtained in both cases

  • 43.
    Siegbahn, Per
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta
    Stockholm University, Faculty of Science, Department of Physics.
    The Combined Picture from Theory and Experiments on Water Oxidation, Oxygen Reduction and Proton Pumping2009In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 30, p. 5832-5840Article in journal (Refereed)
    Abstract [en]

     

    In order to illustrate how theory and experiments can be combined, examples are taken from two projects that have been going on for a decade. The goal is to obtain the full mechanistic picture of wateroxidation in photosystem II and proton pumping in cytochrome c oxidase. It is argued that for obtaining a complete description of these processes, both experiments and theoretical calculations are needed. It is obvious that there are aspects, which are out of reach for computations, but there are also key aspects that can not be obtained by experiments. This concerns very short-lived species but also, in the case of photosynthesis in particular, structural information that is presently out of reach. The main contributions from theory in the present cases, is for photosynthesis a mechanism for O–O bond formation including new and improved structures for all S-states, and for proton pumping a plausible and simple mechanism for proton gating. The examples also illustrate that sometimes rather qualitative experimental information can be of highest importance.

  • 44.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Energy Diagrams for Water Oxidation in Photosystem II Using Different Density Functionals2014In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 10, no 1, p. 268-272Article in journal (Refereed)
    Abstract [en]

    The full sequence of intermediates in the water oxidation process in photosystem II has recently been characterized by model calculations, in good agreement with experiments. In the present paper, the energy diagram obtained is used as a benchmark test for several density functionals. Only the results using B3LYP with 15% or 20% show good agreement with experiments. The other functionals tried show errors for some energy levels as large as 20-30 kcal/mol. The reason for these large errors is that the error for three consecutive oxidations of Mn(III) to Mn(IV) accumulates as the cluster is oxidized.

  • 45.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mutations in the D-channel of cytochrome c oxidase causes leakage of the proton pump2014In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 588, no 4, p. 545-548Article in journal (Refereed)
    Abstract [en]

    It has experimentally been found that certain mutations close to the entry point of the proton transfer channel in cytochrome c oxidase stop proton translocation but not the oxygen reduction chemistry. This effect is termed uncoupling. Since the mutations are 20 angstrom away from the catalytic center, this is very surprising. A new explanation for this phenomenon is suggested here, involving a local effect at the entry point of the proton channel, rather than the long range effects suggested earlier. (C) 2013 Federation of European Biochemical Societies.

  • 46.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantum Chemical Studies of Proton-Coupled Electron Transfer in Metalloenzymes2010In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 110, no 12, p. 7040-7061Article, review/survey (Refereed)
  • 47.
    Siegbahn, Per E. M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chen, Shi-Lu
    Stockholm University, Faculty of Science, Department of Physics. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Significant van der Weals Effects in Transition Metal Complexes2010In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 6, no 7, p. 2040-2044Article in journal (Refereed)
    Abstract [en]

    There is, in general, very good experience using hybrid DFT to study mechanisms of enzyme reactions containing transition metals. For redox reactions, the B3LYP* functional, which has 15% exact exchange, has been shown to be particularly accurate. Still, there are some cases which have turned out to be quite difficult with large errors. In the present study, the effects of van der Waals interaction have been investigated for these cases, using the empirical formula of Grimme. The results are encouraging.

  • 48.
    Siegbahn, Per E.M.
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Blomberg, Margareta R.A.
    Stockholm University, Faculty of Science, Department of Physics.
    On the Proton Pumping Mechanism in Cytochrome c Oxidase2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, p. 12772-12780Article in journal (Refereed)
    Abstract [en]

    Two different issues, important for the pumping mechanism of cyctochrome c oxidase, have been addressed in the present study. One of them concerns the nature of two key proton transfer transition states. A simple electrostatic model is used to suggest that the transition state (TS) for transfer to the pump-site should be positively charged, while the one for transfer to the binuclear center should be charge-neutral. The character of the former TS will guarantee that the protons will be pumped to the outside and not return to the inside, while the neutral character of the latter one will allow transfer with a sufficiently low barrier. In the simple electrostatic analysis, leading to this qualitative picture of the pumping process, the results from the kinetic experiments are strictly followed, but it is at least as important to follow the fundamental requirements for pumping. In this perspective, the uncertainties in the quantitative analysis should be rather unimportant for the emerging qualitative picture of the pumping mechanism. The second problem addressed concerns the purpose of the K-channel. It is argued that the reason for the presence of the K-channel could be that protons cannot pass through the binuclear center at some stage of pumping. Barriers and water binding energies were computed using hybrid density functional theory (DFT) to investigate this question.

1 - 48 of 48
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