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Sason Shaik - One of the best experts on this subject based on the ideXlab platform.

  • can ferric superoxide act as a potential oxidant in p450cam qm mm investigation of hydroxylation epoxidation and sulfoxidation
    Journal of the American Chemical Society, 2011
    Co-Authors: Wenzhen Lai, Sason Shaik
    Abstract:

    In view of recent reports of high reactivity of ferric-superoxide species in Heme and nonHeme systems (Morokuma et al.J. Am. Chem. Soc. 2010, 132, 11993−12005; Que et al.Inorg. Chem. 2010, 49, 3618−3628; Nam et al.J. Am. Chem. Soc. 2010, 132, 5958−5959; J. Am. Chem. Soc. 2010, 132, 10668−10670), we use herein combined quantum mechanics/molecular mechanics (QM/MM) methods to explore the potential reactivity of P450cam ferric-superoxide toward hydroxylation, epoxidation, and sulfoxidation. The calculations demonstrate that P450 ferric-superoxide is a sluggish oxidant compared with the high-valent oxoiron porphyrin cation-radical species. As such, unlike Heme Enzymes with a histidine axial ligand, the P450 superoxo species does not function as an oxidant in P450cam. The origin of this different behavior of the superoxo species of P450 vis-a-vis other Heme Enzymes like tryptophan 2, 3-dioxygenase (TDO) is traced to the ability of the latter superoxo species to make a stronger FeOO−X (X = H,C) bond and to stab...

  • compound i in Heme thiolate Enzymes a comparative qm mm study
    Journal of Physical Chemistry A, 2008
    Co-Authors: Kyungbin Cho, Etienne Derat, Hajime Hirao, Hui Chen, Maria Angels Carvajal, Shimrit Cohen, Walter Thiel, Sason Shaik
    Abstract:

    This study directly compares the active species of Heme Enzymes, so-called Compound I (Cpd I), across the Heme-thiolate enzyme family. Thus, sixty-four different Cpd I structures are calculated by hybrid quantum mechanical/molecular mechanical (QM/MM) methods using four different cysteine-ligated Heme Enzymes (P450cam, the mutant P450cam-L358P, CPO and NOS) with varying QM region sizes in two multiplicities each. The overall result is that these Cpd I species are similar to each other with regard to many characteristic features. Hence, using the more stable CPO Cpd I as a model for P450 Cpd I in experiments should be a reasonable approach. However, systematic differences were also observed, and it is shown that NOS stands out in most comparisons. By analyzing the electrical field generated by the enzyme on the QM region, one can see that (a) the protein exerts a large influence and modifies all the Cpd I species compared with the gas-phase situation and (b) in NOS this field is approximately planar to the Heme plane, whereas it is approximately perpendicular in the other Enzymes, explaining the deviating results on NOS. The calculations on the P450cam mutant L358P show that the effects of removing the hydrogen bond between the Heme sulfur

  • quantum mechanical molecular mechanical study on the mechanisms of compound i formation in the catalytic cycle of chloroperoxidase an overview on Heme Enzymes
    Journal of Physical Chemistry B, 2008
    Co-Authors: Hui Chen, Etienne Derat, Ilme Schlichting, Hajime Hirao, Sason Shaik
    Abstract:

    The formation of Compound I (Cpd I), the active species of the enzyme chloroperoxidase (CPO), was studied using QM/MM calculation. Starting from the substrate complex with hydrogen peroxide, FeIII−HOOH, we examined two alternative mechanisms on the three lowest spin-state surfaces. The calculations showed that the preferred pathway involves heterolytic O−O cleavage that proceeds via the iron hydroperoxide species, i.e., Compound 0 (Cpd 0), on the doublet-state surface. This process is effectively concerted, with a barrier of 12.4 kcal/mol, and is catalyzed by protonation of the distal OH group of Cpd 0. By comparison, the path that involves a direct O−O cleavage from FeIII−HOOH is less favored. A proton coupled electron transfer (PCET) feature was found to play an important role in the mechanism nascent from Cpd 0. Initially, the O−O cleavage progresses in a homolytic sense, but as soon as the proton is transferred to the distal OH, it triggers an electron transfer from the Heme-oxo moiety to form water a...

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    We have determined the crystal structure of the chloroperoxidase (CPO) hydroperoxo reaction intermediate (CPO compound 0) at 1.75-Å resolution. The intermediate was generated through controlled photoreduction of the CPO oxygen complex during x-ray data collection, which was monitored by recording of the crystal absorption spectra. Initially, the peroxo-anion species was formed and then protonated to yield compound 0. Quantum chemical calculations indicate that the peroxo-anion species is not stable and collapses instantaneously to compound 0. Compound 0 is present in the ferric low-spin doublet ground state and is characterized by a long OO bond length of 1.5 Å and a FeO bond distance of 1.8 Å, which is also observed in the crystal structure.

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    Characterization of the doublet and quartet states. (A) QM/MM (UB3LYP/B1:CHARMM) potential energy surfaces between the Fe-OOH− and Fe-O2 2- states. (B) The electronic configurations of the doublet and quartet states of Fe-OOH−.

Ilme Schlichting - One of the best experts on this subject based on the ideXlab platform.

  • quantum mechanical molecular mechanical study on the mechanisms of compound i formation in the catalytic cycle of chloroperoxidase an overview on Heme Enzymes
    Journal of Physical Chemistry B, 2008
    Co-Authors: Hui Chen, Etienne Derat, Ilme Schlichting, Hajime Hirao, Sason Shaik
    Abstract:

    The formation of Compound I (Cpd I), the active species of the enzyme chloroperoxidase (CPO), was studied using QM/MM calculation. Starting from the substrate complex with hydrogen peroxide, FeIII−HOOH, we examined two alternative mechanisms on the three lowest spin-state surfaces. The calculations showed that the preferred pathway involves heterolytic O−O cleavage that proceeds via the iron hydroperoxide species, i.e., Compound 0 (Cpd 0), on the doublet-state surface. This process is effectively concerted, with a barrier of 12.4 kcal/mol, and is catalyzed by protonation of the distal OH group of Cpd 0. By comparison, the path that involves a direct O−O cleavage from FeIII−HOOH is less favored. A proton coupled electron transfer (PCET) feature was found to play an important role in the mechanism nascent from Cpd 0. Initially, the O−O cleavage progresses in a homolytic sense, but as soon as the proton is transferred to the distal OH, it triggers an electron transfer from the Heme-oxo moiety to form water a...

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    We have determined the crystal structure of the chloroperoxidase (CPO) hydroperoxo reaction intermediate (CPO compound 0) at 1.75-Å resolution. The intermediate was generated through controlled photoreduction of the CPO oxygen complex during x-ray data collection, which was monitored by recording of the crystal absorption spectra. Initially, the peroxo-anion species was formed and then protonated to yield compound 0. Quantum chemical calculations indicate that the peroxo-anion species is not stable and collapses instantaneously to compound 0. Compound 0 is present in the ferric low-spin doublet ground state and is characterized by a long OO bond length of 1.5 Å and a FeO bond distance of 1.8 Å, which is also observed in the crystal structure.

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    Characterization of the doublet and quartet states. (A) QM/MM (UB3LYP/B1:CHARMM) potential energy surfaces between the Fe-OOH− and Fe-O2 2- states. (B) The electronic configurations of the doublet and quartet states of Fe-OOH−.

Etienne Derat - One of the best experts on this subject based on the ideXlab platform.

  • compound i in Heme thiolate Enzymes a comparative qm mm study
    Journal of Physical Chemistry A, 2008
    Co-Authors: Kyungbin Cho, Etienne Derat, Hajime Hirao, Hui Chen, Maria Angels Carvajal, Shimrit Cohen, Walter Thiel, Sason Shaik
    Abstract:

    This study directly compares the active species of Heme Enzymes, so-called Compound I (Cpd I), across the Heme-thiolate enzyme family. Thus, sixty-four different Cpd I structures are calculated by hybrid quantum mechanical/molecular mechanical (QM/MM) methods using four different cysteine-ligated Heme Enzymes (P450cam, the mutant P450cam-L358P, CPO and NOS) with varying QM region sizes in two multiplicities each. The overall result is that these Cpd I species are similar to each other with regard to many characteristic features. Hence, using the more stable CPO Cpd I as a model for P450 Cpd I in experiments should be a reasonable approach. However, systematic differences were also observed, and it is shown that NOS stands out in most comparisons. By analyzing the electrical field generated by the enzyme on the QM region, one can see that (a) the protein exerts a large influence and modifies all the Cpd I species compared with the gas-phase situation and (b) in NOS this field is approximately planar to the Heme plane, whereas it is approximately perpendicular in the other Enzymes, explaining the deviating results on NOS. The calculations on the P450cam mutant L358P show that the effects of removing the hydrogen bond between the Heme sulfur

  • quantum mechanical molecular mechanical study on the mechanisms of compound i formation in the catalytic cycle of chloroperoxidase an overview on Heme Enzymes
    Journal of Physical Chemistry B, 2008
    Co-Authors: Hui Chen, Etienne Derat, Ilme Schlichting, Hajime Hirao, Sason Shaik
    Abstract:

    The formation of Compound I (Cpd I), the active species of the enzyme chloroperoxidase (CPO), was studied using QM/MM calculation. Starting from the substrate complex with hydrogen peroxide, FeIII−HOOH, we examined two alternative mechanisms on the three lowest spin-state surfaces. The calculations showed that the preferred pathway involves heterolytic O−O cleavage that proceeds via the iron hydroperoxide species, i.e., Compound 0 (Cpd 0), on the doublet-state surface. This process is effectively concerted, with a barrier of 12.4 kcal/mol, and is catalyzed by protonation of the distal OH group of Cpd 0. By comparison, the path that involves a direct O−O cleavage from FeIII−HOOH is less favored. A proton coupled electron transfer (PCET) feature was found to play an important role in the mechanism nascent from Cpd 0. Initially, the O−O cleavage progresses in a homolytic sense, but as soon as the proton is transferred to the distal OH, it triggers an electron transfer from the Heme-oxo moiety to form water a...

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    We have determined the crystal structure of the chloroperoxidase (CPO) hydroperoxo reaction intermediate (CPO compound 0) at 1.75-Å resolution. The intermediate was generated through controlled photoreduction of the CPO oxygen complex during x-ray data collection, which was monitored by recording of the crystal absorption spectra. Initially, the peroxo-anion species was formed and then protonated to yield compound 0. Quantum chemical calculations indicate that the peroxo-anion species is not stable and collapses instantaneously to compound 0. Compound 0 is present in the ferric low-spin doublet ground state and is characterized by a long OO bond length of 1.5 Å and a FeO bond distance of 1.8 Å, which is also observed in the crystal structure.

  • structure and quantum chemical characterization of chloroperoxidase compound 0 a common reaction intermediate of diverse Heme Enzymes
    Proceedings of the National Academy of Sciences of the United States of America, 2007
    Co-Authors: K. Kühnel, Etienne Derat, Jordan Terner, Sason Shaik, Ilme Schlichting
    Abstract:

    Characterization of the doublet and quartet states. (A) QM/MM (UB3LYP/B1:CHARMM) potential energy surfaces between the Fe-OOH− and Fe-O2 2- states. (B) The electronic configurations of the doublet and quartet states of Fe-OOH−.

Sam P De Visser - One of the best experts on this subject based on the ideXlab platform.

  • how does replacement of the axial histidine ligand in cytochrome c peroxidase by nδ methyl histidine affect its properties and functions a computational study
    International Journal of Molecular Sciences, 2020
    Co-Authors: Calvin W Z Lee, Qadri M E Mubarak, Anthony P Green, Sam P De Visser
    Abstract:

    Heme peroxidases have important functions in nature related to the detoxification of H2O2. They generally undergo a catalytic cycle where, in the first stage, the iron(III)–Heme–H2O2 complex is converted into an iron(IV)–oxo–Heme cation radical species called Compound I. Cytochrome c peroxidase Compound I has a unique electronic configuration among Heme Enzymes where a metal-based biradical is coupled to a protein radical on a nearby Trp residue. Recent work using the engineered Nδ-methyl histidine-ligated cytochrome c peroxidase highlighted changes in spectroscopic and catalytic properties upon axial ligand substitution. To understand the axial ligand effect on structure and reactivity of peroxidases and their axially Nδ-methyl histidine engineered forms, we did a computational study. We created active site cluster models of various sizes as mimics of horseradish peroxidase and cytochrome c peroxidase Compound I. Subsequently, we performed density functional theory studies on the structure and reactivity of these complexes with a model substrate (styrene). Thus, the work shows that the Nδ-methyl histidine group has little effect on the electronic configuration and structure of Compound I and little changes in bond lengths and the same orbital occupation is obtained. However, the Nδ-methyl histidine modification impacts electron transfer processes due to a change in the reduction potential and thereby influences reactivity patterns for oxygen atom transfer. As such, the substitution of the axial histidine by Nδ-methyl histidine in peroxidases slows down oxygen atom transfer to substrates and makes Compound I a weaker oxidant. These studies are in line with experimental work on Nδ-methyl histidine-ligated cytochrome c peroxidases and highlight how the hydrogen bonding network in the second coordination sphere has a major impact on the function and properties of the enzyme.

  • understanding how prolyl 4 hydroxylase structure steers a ferryl oxidant toward scission of a strong c h bond
    Journal of the American Chemical Society, 2017
    Co-Authors: Amy Timmins, Maud Saintandre, Sam P De Visser
    Abstract:

    Prolyl-4-hydroxylase (P4H) is a non-Heme iron hydroxylase that regio- and stereospecifically hydroxylates proline residues in a peptide chain into R-4-hydroxyproline, which is essential for collagen cross-linking purposes in the human body. Surprisingly, in P4H, a strong aliphatic C–H bond is activated, while thermodynamically much weaker aliphatic C–H groups, that is, at the C3 and C5 positions, are untouched. Little is known on the origins of the high regio- and stereoselectivity of P4H and many non-Heme and Heme Enzymes in general, and insight into this matter may be relevant to Biotechnology as well as Drug Development. The active site of the protein contains two aromatic residues (Tyr140 and Trp243) that we expected to be crucial for guiding the regioselectivity of the reaction. We performed a detailed quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) study on wild-type and mutant structures. The work shows that Trp243 is involved in key protein loop–loop interactions that aff...

  • how does the axial ligand of cytochrome p450 biomimetics influence the regioselectivity of aliphatic versus aromatic hydroxylation
    Chemistry: A European Journal, 2009
    Co-Authors: Sam P De Visser, Laleh Tahsini
    Abstract:

    The catalytic activity of high- valent iron-oxo active species of Heme Enzymes is known to be dependent on the nature of the axial ligand trans to the iron-oxo group. In a similar fash- ion, experimental studies on iron-oxo porphyrin biomimetic systems have shown a significant axial ligand effect on ethylbenzene hydroxylation, with an axial acetonitrile ligand leading to phenyl hydroxylation products and an axial chloride anion giving predomi- nantly benzyl hydroxylation products. To elucidate the fundamental factors that distinguish this regioselectivity re- versal in iron-oxo porphyrin catalysis, we have performed a series of density functional theory calculations on the hydroxylation of ethylbenzene by (Fe IV =OA + C)L) (Por = porphyrin; L = NCCH3 or Cl ), which affords 1-phe- nylethanol and p-ethylphenol products. The calculations confirm the experi- mentally determined product distribu- tions. Furthermore, a detailed analysis of the electronic differences between the two oxidants shows that their re- versed regioselectivity is a result of dif- ferences in orbital interactions between the axial ligand and iron-oxo porphy- rin system. In particular, three high- lying orbitals (p*xz, p*yz and a2u), which are singly occupied in the reactant complex, are stabilised with an anionic ligand such as Cl, which leads to en- hanced HOMO-LUMO energy gaps. As a consequence, reactions leading to cationic intermediates through the two- electron reduction of the metal centre are disfavoured. The aliphatic hydrox- ylation mechanism, in contrast, is a radical process in which only one elec- tron is transferred in the rate-determin- ing transition state, which means that the effect of the axial ligand on this mechanism is much smaller.

  • propene activation by the oxo iron active species of taurine α ketoglutarate dioxygenase taud enzyme how does the catalysis compare to Heme Enzymes
    Journal of the American Chemical Society, 2006
    Co-Authors: Sam P De Visser
    Abstract:

    Density functional calculations on the oxygenation reaction of propene by a model for taurine/α-ketoglutarate dioxygenase (TauD) enzyme are presented. The oxo-iron active species of TauD is shown to be a powerful and aggressive oxidant, which is able to hydroxylate C−H bonds and epoxidize CC bonds with low barriers. In the case of propene oxygenation, the hydroxylation and epoxidation mechanisms are competitive on a dominant quintet spin state surface. We have compared the mechanism and thermodynamics of TauD with oxo-iron Heme catalysts, such as the cytochromes P450, and found some critical differences. The TauD model is found to be much more reactive toward oxygenation of substrates than oxo-iron complexes in a Heme environment with much lower reaction barriers. We have analyzed this and assigned this to the strength of the O−H bond formed after hydrogen abstraction from a substrate, which is at least 10 kcal mol-1 stronger in five-coordinated oxo-iron nonHeme complexes than in six-coordinated oxo-iron ...

K. Kühnel - One of the best experts on this subject based on the ideXlab platform.