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  • 1. Bassan, A.
    et al.
    Zou, W. B.
    Reyes, E.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Cordova, A.
    The origin of stereoselectivity in primary amino acid catalyzed intermolecular Aldol reactions2005In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 44, no 43, p. 7028-7032Article in journal (Refereed)
  • 2.
    Chen, Shilu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Fang, Wei-Hai
    Beijing Normal University, College of Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Insights into the Transition States and Mechanism of Alkaline Phosphatase Reaction from the DFT CalculationsManuscript (Other academic)
  • 3.
    Chen, Shilu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Fang, Wei-Hai
    Beijing Normal Univ, Coll Chem.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Reaction mechanism of the binuclear zinc enzyme glyoxalase II: A theoretical study2009In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 103, no 2, p. 274-281Article in journal (Refereed)
    Abstract [en]

    The glyoxalase system catalyzes the conversion of toxic methylglyoxal to nontoxic d-lactic acid using glutathione (GSH) as a coenzyme. Glyoxalase II (GlxII) is a binuclear Zn enzyme that catalyzes the second step of this conversion, namely the hydrolysis of S-d-lactoylglutathione, which is the product of the Glyoxalase I (GlxI) reaction. In this paper we use density functional theory method to investigate the reaction mechanism of GlxII. A model of the active site is constructed on the basis of the X-ray crystal structure of the native enzyme. Stationary points along the reaction pathway are optimized and the potential energy surface for the reaction is calculated. The calculations give strong support to the previously proposed mechanism. It is found that the bridging hydroxide is capable of performing nucleophilic attack at the substrate carbonyl to form a tetrahedral intermediate. This step is followed by a proton transfer from the bridging oxygen to Asp58 and finally C–S bond cleavage. The roles of the two zinc ions in the reaction mechanism are analyzed. Zn2 is found to stabilize the charge of tetrahedral intermediate thereby lowering the barrier for the nucleophilic attack, while Zn1 stabilizes the charge of the thiolate product, thereby facilitating the C–S bond cleavage. Finally, the energies involved in the product release and active-site regeneration are estimated and a new possible mechanism is suggested.

  • 4.
    Chen, Shilu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Fang, Wei-Hai
    Beijing Normal Univ, Coll Chem.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Technical aspects of quantum chemical modeling of enzymatic reactions: the case of phosphotriesterase2008In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 120, no 4-6, p. 515-522Article in journal (Refereed)
    Abstract [en]

    Quantum chemical methods are today a powerful tool in the study of enzymatic reaction mechanisms. In this paper we evaluate the adequacy of some of the technical approximations frequently used in the modeling of enzyme reactions with high level methods. These include the choice of basis set for geometry optimizations and energy evaluation, the choice of dielectric constant to model the enzyme surrounding, and the effects of locking the centers of truncation. As a test case, we choose the phosphotriesterase enzyme, which is a binuclear zinc enzyme that catalyzes the hydrolysis of organophosphate triesters.

  • 5.
    Chen, Shilu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Fang, Wei-Hai
    Beijing Normal Univ, Sch Chem.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Theoretical Study of the Phosphotriesterase Reaction Mechanism2007In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 6, p. 1253-1255Article in journal (Refereed)
    Abstract [en]

    Phosphotriesterase (PTE) is a binuclear zinc enzyme that catalyzes the hydrolysis of extremely toxic organophosphate triesters. In the present work, we have investigated the reaction mechanism of PTE using the hybrid density functional theory method B3LYP. We present a potential energy surface for the reaction and provide characterization of the transition states and intermediates. We used the high resolution crystal structure to construct a model of the active site of PTE, containing the two zinc ions and their first shell ligands. The calculations provide strong support to an associative mechanism for the hydrolysis of phosphotriesters by PTE. No protonation of the leaving group was found to be necessary. In particular, the calculations demonstrate that the nucleophilicity of the bridging hydroxide is sufficient to be utilized in the hydrolysis reaction, a feature that is of importance for a number of other di-zinc enzymes.

  • 6.
    Chen, Shilu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Marino, Tiziana
    Università della Calabria, Dipartimento di Chimica.
    Fang, Wei-Hai
    Beijing Normal Univ, Coll Chem.
    Russo, Nino
    Università della Calabria, Dipartimento di Chimica.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Peptide Hydrolysis by the Binuclear Zinc Enzyme Aminopeptidase from Aeromonas proteolytica: A Density Functional Theory Study2008In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 112, no 8, p. 2494-2500Article in journal (Refereed)
    Abstract [en]

    Aminopeptidase from Aeromonas proteolytica (AAP) is a binuclear zinc enzyme that catalyzes the cleavage of the N-terminal amino acid residue of peptides and proteins. In this study, we used density functional methods to investigate the reaction mechanism of this enzyme. A model of the active site was constructed on the basis of the X-ray crystal structure of the native enzyme, and a model dipeptide was used as a substrate. It was concluded that the hydroxide is capable of performing a nucleophilic attack at the peptide carbonyl from its bridging position without the need to first become terminal. The two zinc ions are shown to have quite different roles. Zn2 binds the amino group of the substrate, thereby orienting it toward the nucleophile, while Zn1 stabilizes the alkoxide ion of the tetrahedral intermediate, thereby lowering the barrier for the nucleophilic attack. The rate-limiting step is suggested to be the protonation of the nitrogen of the former peptide bond, which eventually leads to the cleavage of the C−N bond.

  • 7. Cho, K. B.
    et al.
    Himo, Fahmi
    Graslund, A.
    Siegbahn, P. E. M.
    The substrate reaction mechanism of class III anaerobic ribonucleotide reductase2001In: Journal of Physical Chemistry B, ISSN 1089-5647, Vol. 105, no 27, p. 6445-6452Article in journal (Refereed)
    Abstract [en]

    The substrate mechanism of class III anaerobic ribonucleotide reductase has been studied using quantum chemical methods. The study is based on the previously suggested mechanism for the aerobic class I enzyme, together with the recently determined X-ray structure of the anaerobic enzyme. The initial steps are similar in the mechanisms of these enzymes, but for the suggested rate-limiting steps there are key differences. In the class I enzyme, the 3 ' -keto group of the substrate is protonated in a step involving formation of a sulfur-sulfur bond between two cysteines, One of these cysteines is not present in the anaerobic enzyme. Instead, carbon dioxide is formed in this step from formate, which is present as a cofactor. In line with previous suggestions from experimental observations, the formate first forms a formyl radical. The next step, where the formyl radical protonates the 3 ' -keto group of the substrate, is suggested to be rate limiting with a calculated total barrier of 19.9 kcal/mol, in reasonable agreement with the experimental rate-limiting barrier of 17 kcal/mol. Zero-point and entropy effects are found to be quite significant in lowering the barrier. The mechanism for the entire cycle is discussed in relation to known experimental facts.

  • 8. Cordova, A.
    et al.
    Sunden, H.
    Bogevig, A.
    Johansson, M.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    The direct catalytic asymmetric alpha-aminooxylation reaction: Development of stereoselective routes to 1,2-diols and 1,2-amino alcohols and density functional calculations2004In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 10, no 15, p. 3673-3684Article, review/survey (Refereed)
    Abstract [en]

    Proline-catalyzed direct asymmetric alpha-aminooxylation of ketones and aldehydes is described. The proline-catalyzed reactions between unmodified ketones or aldehydes and nitrosobenzene proceeded with excellent diastereo- and enantioselectivities. In all cases tested, the corresponding products were isolated with >95% ees. Methyl alkyl ketones were regiospecifically oxidized at the methylene carbon atom to afford enantiomerically pure alpha-aminooxylated ketones. In addition, cyclic ketones could be alpha,alpha'-dioxidized with remarkably high selectivity, furnishing the corresponding diaminooxylated ketones with >99% ees. ne reaction mechanism of the proline-catalyzed direct asymmetric alpha-aminooxylation was investigated, and we performed density functional theory (DFT) calculations in order to investigate the nature of the plausible transition states further. We also screened other organocatalysts for the asymmetric alpha-oxidation reaction and found that several proline derivatives were also able to catalyze the transformation with excellent enantioselectivities. Moreover, stereoselective routes for the synthesis of monoprotected vicinal diols and hydroxyketones were found. In addition, short routes for the direct preparation of enantiomerically pure epoxides and 1,2-amino alcohols are presented. The direct catalytic alpha-oxidation is also a novel route for the stereoselective preparation of beta-adrenoreceptor antagonists.

  • 9. Engstrom, M.
    et al.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Graslund, A.
    Minaev, B.
    Vahtras, Olav
    KTH, Superseded Departments, Biotechnology.
    Ågren, Hans
    KTH, Superseded Departments, Biotechnology.
    Hydrogen bonding to tyrosyl radical analyzed by ab initio g-tensor calculations2000In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 104, no 21, p. 5149-5153Article in journal (Refereed)
    Abstract [en]

    Hydrogen bonding to the tyrosyl radical in ribonucleotide reductase (RNR) has been simulated by a complex between the phenoxyl radical and a water molecule. Multiconfigurational self-consistent field linear response theory was used to calculate the g-tensor of the isolated phenoxyl radical and of the phenoxyl-water model. The relevance of the model was motivated by the fact that spin density distributions and electron paramagnetic resonance (EPR) spectra of the phenoxyl and tyrosyl radicals are very similar. The calculated g-tensor anisotropy of the phenoxyl radical was comparable with experimental findings for tyrosyl in those RNRs where the H-bond is absent: g(x) = 2.0087(2.0087), g(y) = 2.0050(2.0042), and g(z) = 2.0025(2.0020), where the tyrosyl radical EPR data from Escherichia coli RNR are given in parentheses. The hydrogen bonding models reproduced a shift toward a lower g(x) value that was observed experimentally for mouse and herpes simplex virus RNR where the H-bond was detected by electron-nuclear double resonance after deuterium exchange. This decrease could be traced to lower angular momentum and spin-orbit coupling matrix elements between the ground B-2(1) and the first excited B-2(2) states (oxygen lone-pair n to pi(SOMO) excitation) upon hydrogen bonding in a linear configuration. The g(x) value was further decreased by hydrogen bonding in bent configurations due to a blue shift of this excitation.

  • 10. Engstrom, M.
    et al.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Ågren, Hans
    KTH, Superseded Departments, Biotechnology.
    Ab initio g-tensor calculations of the thioether substituted tyrosyl radical in galactose oxidase2000In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 319, no 04-mar, p. 191-196Article in journal (Refereed)
    Abstract [en]

    The tyrosyl radical in galactose oxidase is covalently cross-linked to a neighboring cysteine residue through a thioether bond. The role of this sulfur cross-link has been discussed ever since the crystal structure of the enzyme was solved. In the present work, the ab initio multiconfigurational linear response method is applied to calculate the g-tensor of unsubstituted and thioether substituted phenoxyl radicals. In contrast to some previous interpretations, but in agreement with recent EPR measurements, we find that the sulfur substitution induces only minor shifts in the g-tensor components. The spin distribution retains the odd-alternant pattern of the unsubstituted radical and only a small amount of spin is localized to the sulfur center.

  • 11.
    Georgieva, Polina
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase2008In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 214-218Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of human O6-alkylguanine-DNA alkyltransferase (AGT) is studied using density functional theory. AGT repairs alkylated DNA by directly removing the alkyl group from the O6 position of the guanine. A quantum chemical model of the active site was devised based on the recent crystal structure of the AGT–DNA complex. The potential energy curve is calculated and the stationary points are characterized. It is concluded that the previously proposed reaction mechanism is energetically plausible. In this mechanism, His146 first acts as a water-mediated general base to activate Cys145, which then performs a nucleophilic attack to dealkylate the guanine base.

  • 12.
    Georgieva, Polina
    et al.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Himo, Fahmi
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Quantum Chemical Modeling of Enzymatic Reactions: The Case of Histone Lysine Methyltransferase2010In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 31, no 8, p. 1707-1714Article in journal (Refereed)
    Abstract [en]

    Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N-terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods.

  • 13.
    Georgieva, Polina
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Wu, Qian
    Department of Medicinal Chemistry, University of Michigan, Ann Arbor.
    McLeish, Michael J.
    Department of Medicinal Chemistry, University of Michigan, Ann Arbor.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    The reaction mechanism of phenylethanolamine N-methyltransferase: A density functional theory study2009In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1794, no 12, p. 1831-1837Article in journal (Refereed)
    Abstract [en]

    Hybrid density functional theory methods were used to investigate the reaction mechanism of human phenylethanolamine N-methyltransferase (hPNMT). This enzyme catalyzes the S-adenosyl-L-methionine-dependent conversion of norepinephrine to epinephrine, which constitutes the terminal step in the catecholamine biosynthesis. Several models of the active site were constructed based on the X-ray structure. Geometries of the stationary points along the reaction path were optimized and the reaction barrier and energy were calculated and compared to the experimental values. The calculations demonstrate that the reaction takes place via an S(N)2 mechanism with methyl transfer being rate-limiting, a suggestion supported by mutagenesis studies. Optimal agreement with experimental data is reached using a model in which both active site glutamates; are protonated. Overall, the mechanism of hPNMT is more similar to those of catechol O-methyltransferase and glycine N-methyltransferase than to that of guanidinoacetate N-methyltransferase in which methyl transfer is coupled to proton transfer.

  • 14. Ghobril, Cynthia
    et al.
    Hammar, Peter
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Kodepelly, Sanjeevarao
    Wagner, Alain
    Spiess, Bernard
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Baati, Rachid
    Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydesManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Structure-reactivity studies are performed to explore the reaction mechanism of guanidine-catalyzed intramolecular aldol reaction of ketoaldehydes. A large number of guanidines and guanidine-like catalysts were synthesized and their properties were determined. Kinetic profiles and pKa values of the catalysts were measured and correlated to reaction barriers calculated using density functional theory. The calculations show that the structural rigidity determines the pKa of the guanidines. Although the basicity is a very important factor in the catalyst, it is not sufficient to account for the full catalytic power. The availability of two reaction sites aligned for proton shuttling in the transition states is also an essential feature that helps us rationalize the reactivity pattern observed.

  • 15. Guo, J. D.
    et al.
    Luo, Yi
    KTH, Superseded Departments, Biotechnology.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Density functional theory study of the canthaxanthin and other carotenoid radical cations2002In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 366, no 02-jan, p. 73-81Article in journal (Refereed)
    Abstract [en]

    B3LYP hybrid density functional theory method is employed to study the five carotenoid radical cations of canthaxanthin (1), 7',7'-dimethyl-7'-apo-beta-carotene (2), 8'-apo-beta-carotene-8'-al hydrazone (3), 7',7'-dicyano-7'-apo-beta-carotene (4), and 8'-apo-beta-carotene-8'-al (5). The radicals are characterized by means of their geometries, spin populations, and isotropic hyperfine coupling constants. It is shown that for all the systems, the unpaired spin is delocalized over the whole pi-conjugated system in an odd-alternant pattern. As a result of this, the hyperfine coupling constants are rather low. The radical cations of 1, 2, and 3, have very similar properties to the unsubstituted P-carotene radical, while the dicyano- and aldehyde-substitutions result in significantly different electronic structures.

  • 16. Guo, J. D.
    et al.
    Luo, Yi
    KTH, Superseded Departments, Biotechnology.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    DNA repair by spore photoproduct lyase: A density functional theory study2003In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 107, no 40, p. 11188-11192Article in journal (Refereed)
    Abstract [en]

    Density functional theory calculations using the hybrid functional B3LYP have been performed to probe the energetics of the spore photoproduct lyase (SPL) reactions. This enzyme catalyzes the repair of a thymine dimer caused by UV irradiation of bacterial spore DNA. The calculations support the experimentally suggested mechanism, in which the reaction proceeds through hydrogen atom abstraction from the C6 position of the thymine dimer, followed by beta-scission of the C-C bond linking the two bases. The calculations propose, furthermore, that an inter-thymine hydrogen atom transfer step takes place before the back-transfer of the hydrogen atom from the adenosine cofactor. The last step is shown to be the rate-determining step in the reactions.

  • 17.
    Guo, Jingdong
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Catalytic mechanism of pyruvate-formate lyase revisited2004In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 108, no 39, p. 15347-15354Article in journal (Refereed)
    Abstract [en]

    The catalytic mechanism of the glycyl-radical-containing enzyme pyruvate-formate lyase (PFL) is investigated using high-level quantum chemical methods. PFL catalyzes the reversible conversion of pyruvate and coenzyme A (CoA) into formate and acetylated CoA. Large models are employed, based on a recent X-ray crystal structure of PFL in complex with the pyruvate substrate. The rate-limiting step is shown to be the homolytic C1-C2 bond cleavage of pyruvate, which occurs after the attack of the Cys418 radical on the carbonyl carbon of pyruvate. For the acetylation of CoA, we propose a new mechanism, in which the released formyl radical anion abstracts a hydrogen atom directly from CoA. This way, the acetyl group transfer from Cys418 becomes facile. The full potential energy curve for the PFL reactions is presented.

  • 18.
    Hammar, Peter
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Córdova, Armando
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Density Functional Theory Study of the Stereoselectivity in Small Peptide-Catalyzed Intermolecular Aldol Reactions2008In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, p. 1617-1621Article in journal (Refereed)
    Abstract [en]

    The origins of the stereoselection of the dipeptide-catalyzed intermolecular aldol reaction are explored by means of hybrid density functional theory. Transition states were located for the (S)-ala-(S)-ala-catalyzed aldol reaction with cyclohexanone as the donor and benzaldehyde as the acceptor. The calculations reproduce the experimental trends very satisfactorily. It is demonstrated that the main Source of stereoselectivity is the interaction of the N-terminal amino acid side chain of the dipeptide with the cyclohexene ring.

  • 19.
    Hammar, Peter
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Ghobril, Cynthia
    Wagner, Alain
    Baati, Rachid
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Theoretical Mechanistic Study of the TBD-Catalyzed Intramolecular Aldol Reaction of Ketoaldehydes2010In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 14, p. 4728-4736Article in journal (Refereed)
    Abstract [en]

    The intramolecular aldol reaction of acyclic ketoaldehydes catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is investigated using density functional theory calculations. Compared to the aldol reaction catalyzed by proline, the use of TBD provides a unique and unusual complete switch of product selectivity. Three mechanistic pathways are proposed and evaluated. In the favored mechanism TBD catalyzes the reaction through proton transfer in two steps, enolization and C-C bond formation. The computationally predicted stereochemical outcome of the reaction is in agreement with experimental findings. Additionally, these studies provide new insights into the activation mode of bifunctional guanidine catalysts in aldol reactions.

  • 20.
    Hammar, Peter
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Marcelli, Tommaso
    Van't Hoff Institute of Molecular Sciences, University of Amsterdam.
    Hiemstra, Henk
    Van't Hoff Institute of Molecular Sciences, University of Amsterdam.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry reaction: Mechanism and Enantioselectivity2007In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 17-18, p. 2537-2548Article in journal (Refereed)
    Abstract [en]

    We report a density functional theory investigation of the enantioselective Cinchona thiourea-catalyzed Henry reaction of aromatic aldehydes with nitromethane. We show that two pathways (differing in the binding modes of the reactants to the catalyst) are possible for the formation of the C-C bond, and that they have comparable reaction barriers. The enantioselectivity is investigated, and our results are in agreement with the experimentally observed solvent dependence of the reaction.

  • 21. Han, W. G.
    et al.
    Liu, T. Q.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Toutchkine, A.
    Bashford, D.
    Hahn, K. M.
    Noodleman, L.
    A theoretical study of the UV/visible absorption and emission solvatochromic properties of solvent-sensitive dyes2003In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 4, no 10, p. 1084-1094Article in journal (Refereed)
    Abstract [en]

    Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, incorporated with the conductor-like screening model (COSMO) and the self-consistent reaction field (SCRF) methods, we have studied the solvatochromic shifts of both the absorption and emission bands of four solvent sensitive dyes in different solutions. The dye molecules studies here are: S-TBA merocyanine, Abdel-Halim's merocyanine, the rigidified amino-coumarin C153, and Nile red. These dyes were selected because they exemplify different structural features likely to impact the solvent-sensitive fluorescence of push-pull, or merocyanine, fluorophores. All trends of the blue or red shifts were correctly predicted, comparing with the experimental observations. Explicit h-bonding interactions were also considered in several protic solutions like H2O, methanol and ethanol, showing that including explicit H-bonding solvent molecule(s) in the calculations is important to obtain the correct order of the excitation and emission energies. The geometries, electronic structures, dipole moments, and intra- and intermolecular charge transfers of the dyes in different solvents are also discussed.

  • 22.
    Himo, Fahmi
    KTH, Superseded Departments, Biotechnology.
    Catalytic mechanism of benzylsuccinate synthase, a theoretical study2002In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 106, no 31, p. 7688-7692Article in journal (Refereed)
    Abstract [en]

    Density functional theory calculations using the hybrid functional B3LYP have been performed to study the catalytic mechanism of benzylsuccinate synthase. This enzyme catalyzes the novel addition of the methyl carbon of toluene to fumarate, forming benzylsuccinate and thereby initiating the anaerobic metabolism of toluene in denitrifying bacteria. Benzylsuccinate synthase was suggested to contain a stable glycyl radical, based on sequence similarity to the two known glycyl radical containing enzymes pyruvate-formate lyase and class III anaerobic ribonucleotide reductase. This suggestion was recently confirmed by electron paramagnetic resonance experiments. The calculations demonstrate that an overall homolytic radical mechanism is thermodynamic ally very plausible. The radical is transferred from the stable glycyl radical to toluene via a cysteinyl radical in two hydrogen atom transfer steps, The rate-limitin, step is shown to he the addition of benzyl radical to fumarate, forming a benzylsuccinyl radical intermediate. A full potential energy surface for the benzylsuccinate synthase reactions is presented.

  • 23.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    C-C bond formation and cleavage in radical enzymes, a theoretical perspective2005In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1707, no 1, p. 24-33Article, review/survey (Refereed)
    Abstract [en]

    Quantum chemical methods are today a viable tool ill the Study of enzyme catalysis. The development of new density functional techniques and the enormous advancement in computer power have made it possible to accurately describe active sites of enzymes. This review gives a brief account of the methods and models used in this field. Three specific enzymes are discussed: pyruvate-formate lyase (PFL), spore photoproduct lyase (SPL), and benzylsuccinate synthase (BSS). What these enzymes have in common is that they use radical chemistry to catalyze C-C bond formation or cleavage reactions.

  • 24. Himo, Fahmi
    Density functional theory study of the beta-carotene radical cation2001In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 105, no 33, p. 7933-7937Article in journal (Refereed)
    Abstract [en]

    The hybrid density functional theory method B3LYP is employed to study the beta -carotene radical cation. The radical is characterized by means of its geometry, spin distribution, and isotropic and anisotropic hyperfine coupling constants. It is shown that the spin is delocalized over the whole pi -conjugated system, including the double bonds of the headgroups. This delocalization results in methyl hyperfine coupling constants lower than 9 MHz, in excellent agreement with recent experimental couplings of the carotene radical in Photosystem II and in vitro, but in conflict with previous theoretical calculations. It is also demonstrated that rotation of the headgroups can affect the properties of the radical, in particular the spin delocalization to the ring.

  • 25.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Quantum chemical modeling of enzyme active sites and reaction mechanisms2006In: Theoretical Chemistry accounts, ISSN 1432-881X, E-ISSN 1432-2234, Vol. 116, no 03-jan, p. 232-240Article in journal (Refereed)
    Abstract [en]

    Density functional methods, in particular the B3LYP functional, together with the explosive enhancement of computational power, have in the last 5 years or so made it possible to model enzyme active sites and reaction mechanisms in a quite realistic way. Many mechanistic problems have indeed been addressed and solved. This review gives a brief account of the methods and models used to study enzyme active sites and their reaction mechanisms using quantum chemical methods. Examples are given from our recent work in this field. Future perspectives of the field are discussed.

  • 26. Himo, Fahmi
    Stability of protein-bound glycyl radical: a density functional theory study2000In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 328, no 3, p. 270-276Article in journal (Refereed)
    Abstract [en]

    Density functional theory is used to study different models of the glycyl radical in proteins. The radical is characterized by means of the C-alpha-H bond strength, geometry, spin distribution, and hyperfine parameters. It is shown that, due to substituent effects from the peptide bond, the protein-bound glycyl radical is less stable than the nonprotein-bound one. This effect is of great importance for the biological function of the glycyl radical. The capto-dative resonance stabilization is confirmed, and new resonances are suggested to arise due to the peptide bond, resulting in further delocalization of the unpaired spin.

  • 27.
    Himo, Fahmi
    et al.
    KTH, Superseded Departments, Biotechnology.
    Demko, Z. P.
    Noodleman, L.
    Density functional theory study of the intramolecular 2+3 cycloaddition of azide to nitriles2003In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 68, no 23, p. 9076-9080Article in journal (Refereed)
    Abstract [en]

    Density functional theory calculations using the hybrid functional B3LYP have been performed to study tetrazole formation by intramolecular [2 + 3] dipolar cycloaddition of organic azides and nitriles. Experimental reactivity trends are explained and rationalized in terms of a number of parameters, such as strain, tether length, and solvation and entropy effects. Interestingly, no correlation was found between the overall free energies and the free energies of activation of the reactions, due to the significant difference in strain and geometry between the transition states and products.

  • 28. Himo, Fahmi
    et al.
    Demko, Z. P.
    Noodleman, L.
    Sharpless, K. B.
    Mechanisms of tetrazole formation by addition of azide to nitriles2002In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, no 41, p. 12210-12216Article in journal (Refereed)
    Abstract [en]

    It is well-known that azide salts can engage nitriles at elevated temperatures to yield tetrazoles; however, there is continued debate as to the mechanism of the reaction. Density functional theory calculations with the hybrid functional B3LYP have been performed to study different mechanisms of tetrazole formation, including concerted cycloaddition and stepwise addition of neutral or anionic azide species. The calculations presented here suggest a previously unsuspected nitrile activation step en route to an imidoyl azide, which then cyclizes to give the tetrazole. The activation barriers are found to correlate strongly with the electron-withdrawing potential of the substituent on the nitrile.

  • 29.
    Himo, Fahmi
    et al.
    KTH, Superseded Departments, Biotechnology.
    Demko, Z. P.
    Noodleman, L.
    Sharpless, K. B.
    Why is tetrazole formation by addition of azide to organic nitriles catalyzed by zinc(II) salts?2003In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 125, no 33, p. 9983-9987Article in journal (Refereed)
    Abstract [en]

    The mechanism by which zinc(II) catalyzes the union of an azide ion with organic nitriles to form tetrazoles is investigated by means of density functional theory using the hybrid functional B3LYP. The calculations indicate that coordination of the nitrile to the zinc ion is the dominant factor affecting the catalysis; this coordination substantially lowers the barrier for nucleophilic attack by azide. Relative reaction rates of catalyzed and uncatalyzed tetrazole formation also provide experimental support for this conclusion.

  • 30. Himo, Fahmi
    et al.
    Eriksson, L. A.
    Blomberg, M. R. A.
    Siegbahn, P. E. M.
    Substituent effects on OH bond strength and hyperfine properties of phenol, as model for modified tyrosyl radicals in proteins2000In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 76, no 6, p. 714-723Article in journal (Refereed)
    Abstract [en]

    Density functional theory is used to investigate the effects of a variety of substituents (CH3, OH, OCH3, SH, SCH3, NH2, NMe2, NO2, F, Cl, CN, and imidazole) on the phenol O-H bond dissociation energy (BDE) and phenoxyl radical hyperfine properties. Substitutions are made at the ortho position to model modified tyrosine residues found in enzymes. The calculations show that besides the electronic effects of the substituents, intramolecular hydrogen bonds between OH and the substituents will contribute considerably to stabilize the parent species. Substituent effects on anisole O-Me bond strengths can thus not correctly describe the effects on ortho-substituted phenol O-H bond strengths, as previously proposed. This fact is supported by a series of calculations on o-substituted anisoles. The odd-alternant spin pattern of the phenoxyl radical is conserved for most of the substitutions. In particular, it is predicted that the cysteine crosslink to tyrosine, present in the radical enzyme galactose oxidase, and the histidine crosslink, present in cytochrome-c oxidase, will only have minor effects on the BDE and the radical hyperfine coupling constants and spin distribution of the tyrosyl radical.

  • 31. Himo, Fahmi
    et al.
    Eriksson, L. A.
    Maseras, F.
    Siegbahn, P. E. M.
    Catalytic mechanism of galactose oxidase: A theoretical study2000In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 122, no 33, p. 8031-8036Article in journal (Refereed)
    Abstract [en]

    Density functional methods, alone and together with molecular mechanics, are used to study the catalytic mechanism of galactose oxidase. This enzyme catalyzes the conversion of primary alcohols to the corresponding aldehydes, coupled with reduction of dioxygen to hydrogen peroxide. It is shown that the proposed mechanism for this enzyme is energetically feasible. In particular the barrier for the postulated rate-limiting hydrogen atom, transfer between the substrate and the tyrosyl radical, located at equatorial Tyr272, is very plausible. We propose that the radical site, prior to the initial proton transfer step, is located at the axial tyrosine (Tyr495). The radical is transferred to the equatorial tyrosine (Tyr272) simultaneously with the proton transfer. It is, furthermore, argued that the electron transfer from the ketyl radical intermediate to Cu(II) cannot be very exothermic, because this would render the oxygen reduction steps rate-limiting. Finally, the cysteine cross-link on the active site tyrosine is shown to have very minor effects on the energetics of the reaction.

  • 32.
    Himo, Fahmi
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Guo, J. D.
    Rinaldo-Matthis, A.
    Nordlund, P.
    Reaction mechanism of deoxyribonucleotidase: A theoretical study2005In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 109, no 42, p. 20004-20008Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of human deoxyribonucleotidase (dN) is studied using high-level quantum-chemical methods. dN catalyzes the dephosphorylation of deoxyribonucleoside monophosphates (dNMPs) to their nucleoside form in human cells. Large quantum models are employed (99 atoms) based on a recent X-ray crystal structure [Rinaldo-Matthis et al. Nat. Struct. Biol. 2002, 9, 779]. The calculations support the proposed mechanism in which Asp41 performs a nucleophilic attack on the phosphate to form a phospho-enzyme intermediate. Asp43 acts in the first step as an acid, protonating the leaving nucleoside, and in the second step as a base, deprotonating the lytic water. No pentacoordinated intermediates could be located.

  • 33.
    Himo, Fahmi
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Lovell, T.
    Hilgraf, R.
    Rostovtsev, V. V.
    Noodleman, L.
    Sharpless, K. B.
    Fokin, V. V.
    Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates2005In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, no 1, p. 210-216Article in journal (Refereed)
    Abstract [en]

    Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(l) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.

  • 34.
    Himo, Fahmi
    et al.
    KTH, Superseded Departments, Biotechnology.
    Noodleman, L.
    Blomberg, M. R. A.
    Siegbahn, P. E. M.
    Relative acidities of ortho-substituted phenols, as models for modified tyrosines in proteins2002In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 106, no 37, p. 8757-8761Article in journal (Refereed)
    Abstract [en]

    The effects of a variety of ortho-substituents (CH3, OH, OCH3, SH, SCH3, NH2, NO2, F, Cl, CN, and imidazole) on the acidity of phenol are investigated using hybrid density functional theory. Substitutions are made at the ortho-position to model modified tyrosine residues found in enzymes. Although the experimental trends are reproduced, the calculations tend to exaggerate the substituent effects. It is shown that the cysteine cross-link to tyrosine, present in the radical enzyme galactose oxidase, has a small effect on the pK(a) of the residue. The histidine cross-link present in cytochrome c oxidase, on the other hand, will contribute more to. lower the pKa. Comparing the substituent effects on the O-H bond strengths and the acidities, no simple correlation is found between the two.

  • 35. Himo, Fahmi
    et al.
    Siegbahn, P. E. M.
    Catalytic mechanism of glyoxalase I: A theoretical study2001In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 123, no 42, p. 10280-10289Article in journal (Refereed)
    Abstract [en]

    Hybrid density functional theory is used to study the catalytic mechanism of human glyoxalase I (GlxI). This zinc enzyme catalyzes the conversion of the hemithioacetal of toxic methylglyoxal and glutathione to nontoxic (S)-D-lactoylglutathione. GlxI can process both diastereomeric forms of the substrate, yielding the same form of the product. As a starting point for the calculations, we use a recent crystal structure of the enzyme in complex with a transition-state analogue, where it was found that the inhibitor is bound directly to the zinc by its hydroxycarbamoyl functions. It is shown that the Zn ligand Glu172 can abstract the substrate Cl proton from the S enantiomer of the substrate, without being displaced from the Zn ion. The calculated activation barrier is in excellent agreement with experimental rates. Analogously, the Zn ligand Glu99 can abstract the proton from the R form of the substrate. To account for the stereochemical findings, it is argued that the S and R reactions cannot be fully symmetric. A detailed mechanistic scheme is proposed.

  • 36.
    Himo, Fahmi
    et al.
    KTH, Superseded Departments, Biotechnology.
    Siegbahn, P. E. M.
    Quantum chemical studies of radical-containing enzymes2003In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 103, no 6, p. 2421-2456Article, review/survey (Refereed)
  • 37. Himo, Fahmi
    et al.
    Siegbahn, P. E. M.
    Very stable ribonucleotide substrate radical relevant for class I ribonucleotide reductase2000In: Journal of Physical Chemistry B, ISSN 1089-5647, Vol. 104, no 31, p. 7502-7509Article in journal (Refereed)
    Abstract [en]

    In recent experimental studies on the E441Q mutant of ribonucleotide reductase, a new substrate radical was discovered on the minute time scale. This radical is kinetically coupled to a cysteine-based radical appearing on the 10 s time scale. In the present study, density functional calculations have been performed to investigate the nature of these radicals. The most interesting result is that a very stable substrate radical was found, which lies outside the normal substrate pathway. This radical is so stable that its creation has to be avoided by the enzyme, or the substrate reactions would be slowed by several orders of magnitude. It is suggested that the enzyme accomplishes this task by considerably straining the mobility of the Cys225 residue. A previously suggested reaction mechanism is modified to take these recent findings into account. The modification does not significantly change the energetics of the model reactions.

  • 38.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Guo, Jing-Dong
    Department of Applied Chemistry, Jiangxi Science and Technology Normal University.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Theoretical Investigation of the First-Shell Mechanism of Nitrile Hydratase2007In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 46, no 12, p. 4850-4856Article in journal (Refereed)
    Abstract [en]

    The first-shell mechanism of nitrile hydratase (NHase) is investigated theoretically using density functional theory. NHases catalyze the conversion of nitriles to amides and are classified into two groups, the non-heme Fe(III) NHases and the non-corrinoid Co(III) NHases. The active site of the non-heme iron NHase comprises a low-spin iron (S = (1)/(2)) with a remarkable set of ligands, including two deprotonated backbone nitrogens and both cysteine-sulfenic and cysteine-sulfinic acids. A widely proposed reaction mechanism of NHase is the first-shell mechanism in which the nitrile substrate binds directly to the low-spin iron in the sixth coordination site. We have used quantum chemical models of the NHase active site to investigate this mechanism. We present potential energy profiles for the reaction and provide characterization of the intermediates and transition-state structures for the NHase-mediated conversion of acetonitrile. The results indicate that the first-shell ligand Cys114-SO- could be a possible base in the nitrile hydration mechanism, abstracting a proton from the nucleophilic water molecule. The generally suggested role of the Fe(III) center as a Lewis acid, activating the substrate toward nucleophilic attack, is shown to be unlikely. Instead, the metal is suggested to provide electrostatic stabilization to the anionic imidate intermediate, thereby lowering the reaction barrier.

  • 39.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Hallberg, B. Martin
    Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Catalytic mechanism of limonene epoxide hydrolase: a theoretical study2005In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, no 41, p. 14339-14347Article in journal (Refereed)
    Abstract [en]

    The catalytic mechanism of limonene epoxide hydrolase (LEH) was investigated theoretically using the density functional theory method B3LYP. LEH is part of a novel limonene degradation pathway found in Rhodococcus erythropolis DCL14, where it catalyzes the hydrolysis of limonene-1,2-epoxide to give limonene-1,2-diol. The recent crystal structure of LEH was used to build a model of the LEH active site composed of five amino acids and a crystallographically observed water molecule. With this model, hydrolysis of different substrates was investigated. It is concluded that LEH employs a concerted general acid/general base-catalyzed reaction mechanism involving protonation of the substrate by Asp101, nucleophilic attack by water on the epoxide, and abstraction of a proton from water by Asp132. Furthermore, we provide an explanation for the experimentally observed regioselective hydrolysis of the four stereoisomers of limonene-1,2-epoxide.

  • 40.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Cyanolysis and Azidolysis of Epoxides by Haloalcohol Dehalogenase: Theoretical Study of the Reaction Mechanism and Origins of Regioselectivity2008In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, no 17, p. 4973-4982Article in journal (Refereed)
    Abstract [en]

    Haloalcohol dehalogenase HheC catalyzes the reversible dehalogenation of vicinal haloalcohols to form epoxides and free halides. In addition, HheC is able to catalyze the irreversible and highly regioselective ring-opening of epoxides with nonhalide nucleophiles, such as CN- and N-3(-). For azidolysis of aromatic epoxides, the regioselectivity observed with HheC is opposite to the regioselectivity of the nonenzymatic epoxide-opening. This, together with a relatively broad substrate specificity, makes HheC a promising tool for biocatalytic applications. We have designed large quantum chemical models of the HheC active site and used density functional theory to study the reaction mechanism of the HheC-catalyzed ring-opening of (R)-styrene oxide with the nucleophiles CN- and N3-. Both the cyanolysis and the azidolysis reactions are shown to take place in a single concerted step. The results support the suggested role of the putative Ser132-Tyr145-Arg149 catalytic triad, where Tyr145 acts as a general acid, donating a proton to the substrate, and Arg149 interacts with Tyr145 and facilitates proton abstraction, while Ser132 positions the substrate and reduces the barrier for epoxide opening through interaction with the emerging oxyanion of the substrate. We have also studied the regioselectivity of (R)-styrene oxide opening for both the cyanolysis and the azidolysis reactions. The employed active site model was shown to be able to reproduce the experimentally observed beta-regioselectivity of HheC. In silico mutations of various groups in the HheC active site model were performed to elucidate the important factors governing the regioselectivity.

  • 41.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Insights into the Reaction Mechanism of Soluble Epoxide Hydrolase from Theoretical Active Site Mutants2006In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 42, p. 21299-21310Article in journal (Refereed)
    Abstract [en]

    Density functional theory calculations of active site mutants are used to gain insights into the reaction mechanism of the soluble epoxide hydrolases (sEHs). The quantum chemical model is based on the X-ray crystal structure of the human soluble epoxide hydrolase. The role of two conserved active site tyrosines is explored through in silico single and double mutations to phenylalanine. Full potential energy curves for hydrolysis of (1S,2S)-beta-methylstyrene oxide are presented. The results indicate that the two active site tyrosines act in concert to lower the activation barrier for the alkylation step. For the wild-type and three different tyrosine mutant models, the regioselectivity of epoxide opening is compared for the substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide. An additional part of our study focuses on the importance of the catalytic histidine for the alkylation half-reaction. Different models are presented to explore the protonation state of the catalytic histidine in the alkylation step and to evaluate the possibility of an interaction between the nucleophilic aspartate and the catalytic histidine.

  • 42.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    On the Role of Tyrosine as Catalytic Base in Nitrile Hydratase2008In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, no 22, p. 3452-3459Article in journal (Refereed)
    Abstract [en]

    Nitrile Hydratases (NHases) catalyze the conversion of nitriles to their corresponding amides. Two NHase classes exist, the Fe-III-NHases and the Co-III-NHases. Both harbour an intriguing active site, with a low-spin metal ion coordinated to deprotonated back-bone amides and oxidized cysteine residues. So far it has not been possible to conclusively determine the reaction mechanism of NHase. Here we employ density functional theory to investigate the recent proposal that a fully conserved second-shell tyrosine residue is the catalytic base of nitrile hydratase (J. Biol. Chem. 2007, 282, 7397-7404). In the proposed mechanism, the tyrosine is suggested to be in the tyrosinate state and to mediate nitrile hydration through activation of a water molecule, which attacks the metal-bound substrate. We have explored this mechanism employing quantum chemical active site models on the basis of the Co-III-NHase from P. thermophila JCM 3095 and the Fe-III-NHase from R. erythropolis N-771. Potential energy curves and optimized transition states are presented. The computed barriers for the two models are a few kcal/mol above the experimental value, indicating that the conserved second-shell tyrosine could function as the catalytic base of NHase. To further evaluate the likelihood of this mechanism, we estimated the pK(a) value of the second-shell tyrosine in each model. We also provide estimates of the energy involved in the exchange of a metal-bound water molecule with a nitrile substrate.

  • 43.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Quantum Chemical Modeling of the Dehalogenation Reaction of Haloalcohol Dehalogenase2008In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, no 7, p. 1129-1137Article in journal (Refereed)
    Abstract [en]

    The dehalogenation reaction of haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 was investigated theoretically using hybrid density functional theory methods. HheC catalyzes the enantioselective conversion of halohydrins into their corresponding epoxides. The reaction is proposed to be mediated by a catalytic Ser132-Tyr145-Arg149 triad, and a distinct halide binding site is suggested to facilitate halide displacement by stabilizing the free ion. We investigated the HheC-mediated dehalogenation of (R)-2-chloro-1-phenylethanol using three quantum chemical models of various sizes. The calculated barriers and reaction energies give support to the suggested reaction mechanism. The dehalogenation occurs in a single concerted step, in which Tyr145 abstracts a proton from the halohydrin substrate and the substrate oxyanion displaces the chloride ion, forming the epoxide. Characterization of the involved stationary points is provided. Furthermore, by using three different models of the halide binding site, we are able to assess the adopted modeling methodology.

  • 44.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Theoretical Investigation of the Second-Shell Mechanism of Nitrile Hydratase2008In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, no 9, p. 1406-1412Article in journal (Refereed)
    Abstract [en]

    Nitrile hydratases (NHases) are biocatalytically important enzymes that are utilized in the industrial production of acrylamide and nicotinamide. There are two different classes of NHases, harbouring either a low-spin Fe-III or a low-spin Co-III ion in the active site, in each case with the same peculiar set of ligands, involving deprotonated backbone amides and oxidized cysteine residues. The detailed reaction mechanism of NHase has not been established yet, but different proposals have been put forward. Depending on the binding site of the substrate, these can be divided into first-shell and second-shell mechanisms, respectively, Recently, we have investigated different first-shell mechanisms using quantum-chemical active-site models based on the iron-dependent NHase (Inorg. Chem. 2007, 46, 4850). Here we continue our investigation of the NHase reaction by exploring two different variations of the second-shell mechanism of the iron-dependent NHase. In the first, a metal-bound hydroxide ion performs a nucleophilic attack on the nitrile substrate, while in the second investigated mechanism, the oxidized cysteine, Cys114-SO-, acts as the nucleophile. We report energies, optimized transition state, and intermediate geometries for both investigated mechanisms. The calculated barriers are similar to the previously reported first-shell mechanism involving Cys114-SO- as catalytic base.

  • 45.
    Hopmann, Kathrin H.
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Theoretical study of the full reaction mechanism of human soluble epoxide hydrolase2006In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 12, no 26, p. 6898-6909Article in journal (Refereed)
    Abstract [en]

    The complete reaction mechanism of soluble epoxide hydrolase (sEH) has been investigated by using the B3LYP density functional theory method. Epoxide hydrolases catalyze the conversion of epoxides to their corresponding vicinal diols. In our theoretical study, the sEH active site is represented by quantum-chemical models that are based on the X-ray crystal structure of human soluble epoxide hydrolase. The trans-substituted epoxide (1S,2S)-beta-methyl styrene oxide has been used as a substrate in the theoretical investigation of the sEH reaction mechanism. Both the alkylation and the hydrolytic half-reactions have been studied in detail. We present the energetics of the reaction mechanism as well as the optimized intermediates and transition-state structures. Full potential energy curves for the reactions involving nucleophilic attack at either the benzylic or the homo-benzylic carbon atom of (1S,2S)-beta-methylstyrene oxide have been computed. The regioselectivity of epoxide opening has been addressed for the two substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide.

  • 46.
    Hopmann, Kathrin Helen
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry (closed 20110512).
    Quantum chemical modeling of enzymatic reactions - applications to epoxide-transforming enzymes2010In: Comprehensive Natural Products II: Chemistry and Biology, Elsevier, 2010, Vol. 8, p. 719-747Chapter in book (Refereed)
  • 47.
    Hopmann, Kathrin
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    A theoretical study of th azidolysis and cyanolysis of epozides by haloalcohol dehalogenaseManuscript (Other academic)
  • 48.
    Ibrahem, Ismail
    et al.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Rios, Ramon
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Vesely, Jan
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Hammar, Peter
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Eriksson, Lars
    Department of Structural Chemistry, Arrhenius Laboratory, Stockholm University.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Córdova, Armando
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University.
    Enantioselective Organocatalytic Hydrophosphination of α,β-Unsaturated Aldehydes2007In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 46, no 24, p. 4507-4510Article in journal (Refereed)
    Abstract [en]

    Keeping it simple: Optically active phosphine derivatives can be obtained in high yields and in up to 99% ee by using simple chiral amines to catalyze the hydrophosphination of α,β-unsaturated aldehydes (see scheme, green sphere = chiral group). The synthetic utility of this highly chemo- and enantioselective transformation was exemplified by the one-pot asymmetric synthesis of β-phosphine oxide acids.

  • 49.
    Kim, Jungwook
    et al.
    Albert Einstein Coll Med.
    Tsai, Ping-Chuan
    Texas A&M Univ, Dept Chem.
    Chen, Shilu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Almo, Steven C.
    Albert Einstein Coll Med.
    Raushel, Frank M.
    Texas A&M Univ, Dept Chem.
    Structure of Diethyl Phosphate Bound to the Binuclear Metal Center of Phosphotriesterase2008In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 47, no 36, p. 9497-9504Article in journal (Refereed)
    Abstract [en]

    The bacterial phosphotriesterase (PTE) from Pseudomonas diminuta catalyzes the hydrolysis of organophosphate esters at rates close to the diffusion limit. X-ray diffraction studies have shown that a binuclear metal center is positioned in the active site of PTE and that this complex is responsible for the activation of the nucleophilic water from solvent. In this paper, the three-dimensional structure of PTE was determined in the presence of the hydrolysis product, diethyl phosphate (DEP), and a product analogue, cacodylate. In the structure of the PTE−diethyl phosphate complex, the DEP product is found symmetrically bridging the two divalent cations. The DEP displaces the hydroxide from solvent that normally bridges the two divalent cations in structures determined in the presence or absence of substrate analogues. One of the phosphoryl oxygen atoms in the PTE−DEP complex is 2.0 Å from the α-metal ion, while the other oxygen is 2.2 Å from the β-metal ion. The two metal ions are separated by a distance of 4.0 Å. A similar structure is observed in the presence of cacodylate. Analogous complexes have previously been observed for the product complexes of isoaspartyl dipeptidase, d-aminoacylase, and dihydroorotase from the amidohydrolase superfamily of enzymes. The experimentally determined structure of the PTE−diethyl phosphate product complex is inconsistent with a recent proposal based upon quantum mechanical/molecular mechanical simulations which postulated the formation of an asymmetrical product complex bound exclusively to the β-metal ion with a metal−metal separation of 5.3 Å. This structure is also inconsistent with a chemical mechanism for substrate hydrolysis that utilizes the bridging hydroxide as a base to abstract a proton from a water molecule loosely associated with the α-metal ion. Density functional theory (DFT) calculations support a reaction mechanism that utilizes the bridging hydroxide as the direct nucleophile in the hydrolysis of organophosphate esters by PTE.

  • 50.
    Liao, Rong-Zhen
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Yu, Jian-Guo
    Himo, Fahmi
    KTH, School of Biotechnology (BIO), Theoretical Chemistry.
    Reaction mechanism of the dinuclear zinc enzyme N-acyl-L-homoserine lactone hydrolase: a quantum chemical study2009In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 48, no 4, p. 1442-1448Article in journal (Refereed)
    Abstract [en]

    N-acyl-L-homoserine lactone hydrolase (AHL lactonase) is a dinuclear zinc enzyme responsible for the hydrolytic ring opening of AHLs, disrupting quorum sensing in bacteria. The reaction mechanism is investigated using hybrid density functional theory. A model of the active site is designed on the basis of the X-ray crystal structure, and stationary points along the reaction pathway are optimized and analyzed. Two possible mechanisms based on two different substrate orientations are considered. The calculations give support to a reaction mechanism that involves two major chemical steps: nucleophilic attack on the substrate carbonyl carbon by the bridging hydroxide and ring opening by direct ester C - O bond cleavage. The roles of the two zinc ions are analyzed. Zn1 is demonstrated to stabilize the charge of the tetrahedral intermediate, thereby facilitating the nucleophilic attack, while Zn2 stabilizes the charge of the alkoxide resulting from the ring opening, thereby lowering the barrier for the C - O bond cleavage.

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