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  • 1.
    Ahlford, Katrin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ryberg, Per
    Eriksson, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nordin, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanistic investigation of enantioswitchable catalysts for asymmetric transfer hydrogenation2010Inngår i: Abstracts of Papers, 239th ACS National Meeting, San Francisco , CA, United States, March 21-25, 2010, Washington: American Chemical Society , 2010Konferansepaper (Annet vitenskapelig)
  • 2.
    Alam, Rauful
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Das, Arindam
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Huang, Genping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Eriksson, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för oorganisk kemi och strukturkemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stereoselective allylboration of imines and indoles under mild conditions. An in situ E/Z isomerization of imines by allylboroxines2014Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 5, nr 7, s. 2732-2738Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Direct allylboration of various acyclic and cyclic aldimine, ketimine and indole substrates was performed using allylboronic acids. The reaction proceeds with very high anti-stereoselectivity for both E and Z imines. The allylboroxines formed by dehydration of allylboronic acids have a dual effect: promoting E/Z isomerization of aldimines and triggering the allylation by efficient electron withdrawal from the imine substrate.

  • 3. Barbion, Julien
    et al.
    Sorin, Geoffroy
    Selkti, Mohamed
    Kellenberger, Esther
    Baati, Rachid
    Santoro, Stefano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Pancrazi, Ange
    Lannou, Marie-Isabelle
    Ardisson, Janick
    Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A2012Inngår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, nr 32, s. 6504-6512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An important feature of the synthesis of salinosporamide A. a potent proteasome inhibitor, is the establishment of the quaternary stereocenter at C3. A new route has been developed based on the methylation of a functionalized pyrrolidinone. Direct methylation reaction led to the unwanted diastereomer: however, by means of a Corey-Chaykovsky reaction followed by LiAlH4 epoxide opening, the desired alcohol was obtained. The pyrrolidinone was elaborated through a key allylation reaction between a tertiary allyltitanium reagent and an aldehyde bearing a spiroketal moiety in alpha-position.

  • 4.
    Binh, Khanh Mai
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanisms of Rh-Catalyzed Oxyfluorination and Oxytrifluoromethylation of Diazocarbonyl Compounds with Hypervalent Fluoroiodine2018Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, nr 5, s. 4483-4492Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reaction mechanisms of rhodium-catalyzed geminal oxyfluorination and oxytrifluoromethylation of diazo-carbonyl compounds with fluoro-benziodoxole and Togni reagents are investigated by means of density functional theory calculations. It is shown that the two reactions follow very similar mechanisms, involving N-2 dissociation to form a Rh-carbene intermediate, alcohol insertion and proton transfer resulting in a stable Rh-enol intermediate, and concerted proton transfer/electrophilic addition of the hypervalent iodine reagent to the enol. Isomerization of the hypervalent iodine takes then place before a ligand coupling affords the final product. The role of the dirhodium catalyst in facilitating the various steps of the reaction is discussed. The presented mechanisms are consistent with available experimental information, and the obtained insights allow for extension to other reactions involving hypervalent iodine reagents.

  • 5. Biswas, Srijit
    et al.
    Dahlstrand, Christian
    Watile, Rahul A.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Atom-Efficient Gold(I)-Chloride-Catalyzed Synthesis of alpha-Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation2013Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 52, s. 17939-17950Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gold(I)-chloride-catalyzed synthesis of -sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated -sulfenylated aldehydes and ketones in 60-97% yield. Secondary aliphatic propargylic alcohols generated -sulfenylated ketones in yields of 47-71%. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3-position, and that the hydride from the alcohol was transferred to the 2-position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2-position of propargylic alcohol was determined by a low-energy, five-membered cyclic protodeauration transition state instead of the strained, four-membered cyclic transition state found for attack at the 3-position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2-hydride shift, generating the final product of the reaction.

  • 6.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Borowski, Tomasz
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Liao, Rong-Zhen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Quantum Chemical Studies of Mechanisms for Metalloenzymes2014Inngår i: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 114, nr 7, s. 3601-3658Artikkel, forskningsoversikt (Fagfellevurdert)
  • 7. Bunrit, Anon
    et al.
    Dahlstrand, Christian
    Olsson, Sandra K.
    Srifa, Pemikar
    Huang, Genping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Orthaber, Andreas
    Sjöberg, Per J. R.
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer2015Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 14, s. 4646-4649Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote S(N)1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.

  • 8. Bunrit, Anon
    et al.
    Dahlstrand, Christian
    Srifa, Pemikar
    Olsson, Sandra K.
    Huang, Genping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Tianjin University, China.
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Uppsala University, Sweden.
    Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer2016Inngår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 27, nr 2, s. 173-176Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A brief overview of the development of direct substitution of the hydroxyl (OH) group of alcohols in our research group is presented. By applying a BrOnsted acid, an intramolecular substitution of the OH group in stereogenic alcohols with chirality transfer was achieved. Noteworthy, the intramolecular substitution has a wide scope in respect to both the nucleophile and also the nucleofuge. A mechanistic study by both experiments and DFT calculations revealed a unique reaction pathway in which the BrOnsted acid operates in a bifunctional manner to promote an S(N)2-type reaction mechanism.

  • 9.
    Bunrit, Anon
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Srifa, Pemikar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dahlstrand, Christian
    Huang, Genping
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Watile, Rahul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate HeterocyclesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The direct intramolecular stereospecific substitution of the hydroxyl group in stereogenic secondary alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five- and six-membered heterocycles in good to excellent yields and high enantiospecificity with water as the only by product. Mechanistic studies using both experiments and calculations have been performed. Rate order determination shows first-order dependences in catalyst, internal nucleophile, and electrophile concentrations, however, independence on external nucleophile and electrophile. Furthermore, phosphinic acid does not promote SN1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activations of both nucleofuge and nucleophile occur in a bridging SN2-type transition state. 

  • 10. Chojnacka, Kinga
    et al.
    Santoro, Stefano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Awartani, Radi
    Richards, Nigel G. J.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Aponick, Aaron
    Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization: implications for strigolactone biosynthesis2011Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, nr 15, s. 5350-5353Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report a new method for constructing the ABC ringsystem of strigolactones, in a single step from a simple linearprecursor by acid-catalyzed double cyclization. The reactionproceeds with a high degree of stereochemical control, whichcan be qualitatively rationalized usingDFT calculations. Ourconcise synthetic approach offers a new model for thinkingabout the (as yet) unknown chemistry that is employed in thebiosynthetic pathways leading to this class of plant hormones.

  • 11. Chowdhury, Sugata
    et al.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Russo, Nino
    Sicilia, Emilia
    Mechanistic investigation of the hydrogenation of O2 by a transfer hydrogenation catalyst2010Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 132, nr 12, s. 4178-4190Artikkel i tidsskrift (Fagfellevurdert)
  • 12. Das, Biswanath
    et al.
    Daver, Henrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Pyrkosz-Bulska, Monika
    Gumienna-Kontecka, Elzbieta
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nordlander, Ebbe
    An Unsymmetric Ligand with a N5O2 Donor Set and Its Corresponding Dizinc Complex: A Structural and Functional Phosphoesterase Model2018Inngår i: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, nr 36, s. 4004-4013Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To mimic the active sites of the hydrolytic enzyme zinc phosphotriesterase, a new dinucleating unsymmetric ligand, PICIMP (2-{[2-hydroxy-5-methyl-3-({[(1-methyl-1H-imidazol-2-yl)methyl](pyridin-2-ylmethyl)amino}methyl)benzyl][(1-methyl-1H-imidazol-2-yl)methyl]amino}acetic acid), has been synthesized and characterized. The hydrolytic efficacy of the complex solution (PICIMP/ZnCl2 = 1:2) has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analogue substrate. Speciation studies were undertaken by potentiometric titrations at varying pH for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; these studies reveal that the dinuclear zinc(II) complexes, [Zn-2(PICIMP)](2+) and [Zn-2(PICIMP)(OH)](+) predominate in solution above pH 4. The obtained pK(a) of 7.44 for the deprotonation of water suggests formation of a bridging hydroxide between the two Zn-II ions. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-10.5 have been performed. The cumulative results indicate the hydroxo-bridged dinuclear Zn-II complex [Zn-2(PICIMP)(mu-OH)](+) as the effective catalyst. Density functional theory calculations were performed to investigate the detailed reaction mechanism. The calculations suggest that the bridging hydroxide becomes terminally coordinated to one of the zinc ions before performing the nucleophilic attack in the reaction.

  • 13. Das, Biswanath
    et al.
    Daver, Henrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Pyrkosz-Bulska, Monika
    Persch, Elke
    Barman, Suman K.
    Mukherjee, Rabindranath
    Gumienna-Kontecka, Elzbieta
    Jarenmark, Martin
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nordlander, Ebbe
    A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)0(2) donor set; A structural and functional model for the active site of zinc phosphoesterases2014Inngår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 132, s. 6-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dinuclear complex [Zn-2(DPCPMP)(pivalate)](C10(4)), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin2-y1)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate(BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn-2(DPCPMP)](2) and [Zn-2(DPCPMP)(OH)1 predominate the solution above pH 4. The relatively high pKa of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand = 0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters triangle H double dagger = 95.6 kJ mol(-1), triangle S double dagger = 44.8 J mo1(-1) K-1, and 6,triangle G double dagger = 108.0 kJ mo1-1. The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn-2(DPCPMP)(mu-OH)] (+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFF). Calculations show that the reaction goes through one concerted step (S(N)2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.

  • 14. Das, Biswanath
    et al.
    Daver, Henrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Singh, Amrendra
    Singh, Reena
    Haukka, Matti
    Demeshko, Serhiy
    Meyer, Franc
    Lisensky, George
    Jarenmark, Martin
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nordlander, Ebbe
    A Heterobimetallic FeIIIMnII Complex of an Unsymmetrical Dinucleating Ligand: A Structural and Functional Model Complex for the Active Site of Purple Acid Phosphatase of Sweet Potato2014Inngår i: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, Vol. 2014, nr 13, s. 2204-2212Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The heterodinuclear mixed-valence complex [FeMn(ICIMP)(OAc)(2)Cl] (1) {H2ICIMP = 2-(N-carboxylmethyl)-[N-(N-methylimidazolyl-2-methyl)aminomethyl]-[6-(N-isopropylmethyl)-[N-(N-methylimidazolyl-2-methyl)]aminomethyl-4-methylphenol], an unsymmetrical N4O2 donor ligand} has been synthesized and fully characterized by several spectroscopic techniques as well as by X-ray crystallography. The crystal structure of the complex reveals that both metal centers in 1 are six-coordinate with the chloride ion occupying the sixth coordination site of the Mn-II ion. The phenoxide moiety of the ICIMP ligand and both acetate ligands bridge the two metal ions of the complex. Mossbauer spectroscopy shows that the iron ion in 1 is high-spin Fe-III. Two quasi-reversible redox reactions for the complex, attributed to the (FeMnII)-Mn-III/(FeMnII)-Mn-II (at -0.67 V versus Fc/Fc(+)) and (FeMnII)-Mn-III/(FeMnIII)-Mn-III (at 0.84 V), were observed by means of cyclic voltammetry. Complex 1, with an Fe-III-Mn-II distance of 3.58 angstrom, may serve as a model for the mixed-valence oxidation state of purple acid phosphatase from sweet potato. The capability of the complex to effect organophosphate hydrolysis (phosphatase activity) has been investigated at different pH levels (5.5-11) by using bis(2,4-dinitrophenyl)phosphate (BDNPP) as the substrate. Density functional theory calculations indicate that the substrate coordinates to the Mn-II ion. In the transition state, a hydroxide ion that bridges the two metal ions becomes terminally coordinated to the Fe-III ion and acts as a nucleophile, attacking the phosphorus center of BDNPP with the concomitant dissociation of the leaving group.

  • 15.
    Daver, Henrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Algarra, Andrés G.
    Rebek, Jr., Julius
    Harvey, Jeremy N.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Toward Accurate Quantum Chemical Modeling of Water-Soluble Self-Assembled CapsulesManuskript (preprint) (Annet vitenskapelig)
  • 16.
    Daver, Henrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Algarra, Andrés G.
    Rebek, Julius
    Harvey, Jeremy N.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mixed Explicit-Implicit Solvation Approach for Modeling of Alkane Complexation in Water-Soluble Self-Assembled Capsules2018Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, nr 39, s. 12527-12537Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The host-guest binding properties of a water-soluble resorcinarene-based cavitand are examined using density functional theory methodology. Experimentally, the cavitand has been observed to self-assemble in aqueous solution into both 1:1 and 2:1 host/guest complexes with hydrophobic guests such as n-alkanes. For n-decane, equilibrium was observed between the 1:1 and 2:1 complexes, while 1:1 complexes are formed with shorter n-alkanes and 2:1 complexes are formed with longer ones. These findings are used to assess the standard quantum chemical methodology. It is first shown that a rather advanced com- putational protocol (B3LYP-D3(BJ)/6-311+G(2d,2p) with COSMO-RS and quasi-rigid-rotor-harmonic-oscillator) gives very large errors. Systematic examination of the various elements of the methodology shows that the error stems from the implicit solvation model. A mixed explicit-implicit solvation protocol is developed that involves a parametrization of the hydration free energy of water such that water cluster formation in water is predicted to be thermoneutral. This new approach is demonstrated to lead to a major improvement in the calculated binding free energies of n-alkanes, reproducing very well the 1:1 versus 2:1 host/guest binding trends.

  • 17.
    Daver, Henrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Das, Biswanath
    Nordlander, Ebbe
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex2016Inngår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 55, nr 4, s. 1872-1882Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Density functional theory calculations have been used to investigate the reaction mechanisms of phosphodiester hydrolysis and transesterification catalyzed by a dinuclear zinc complex of the 2-(N-isopropyl-N-((2-pyridyl)methyl)-aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)methyl)amino-methyl)-4-methylphenol (IPCPMP) ligand, mimicking the active site of zinc phosphotriesterase. The substrates bis(2,4)-dinitrophenyl phosphate (BDNPP) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) were employed as analogues of DNA and RNA, respectively. A number of different mechanistic proposals were considered, with the active catalyst harboring either one or two hydroxide ions. It is concluded that for both reactions the catalyst has only one hydroxide bound, as this option yields lower overall energy barriers. For BDNPP hydrolysis, it is suggested that the hydroxide acts as the nucleophile in the reaction, attacking the phosphorus center of the substrate. For HPNP transesterification, on the other hand, the hydroxide is proposed to act as a Bronsted base, deprotonating the alcohol moiety of the substrate, which in turn performs the nucleophilic attack. The calculated overall barriers are in good agreement with measured rates. Both reactions are found to proceed by essentially concerted associative mechanisms, and it is demonstrated that two consecutive catalytic cycles need to be considered in order to determine the rate-determining free energy barrier.

  • 18.
    Daver, Henrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Harvey, Jeremy N.
    Rebek, Jr., Julius
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule2017Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, nr 43, s. 15494-15503Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dispersion-corrected density functional theory is used to study the cycloaddition reaction between phenyl acetylene and phenyl azide inside a synthetic, self-assembled capsule. The capsule is first characterized computationally and a previously unrecognized structure is identified as being the most stable. Next, an examination of the free energies of host-guest complexes is conducted, considering all possible reagent, solvent and solvent impurity combinations as guests. The experimentally observed relative stabilities of host-guest complexes are quite well reproduced, when the experimental concentrations are taken into account. Experimentally, the presence of the host capsule has been shown to accelerate the cycloaddition reaction and to yield exclusively the 1,4-regioisomer product. Both these observations are reproduced by the calculations. A detailed energy decomposition analysis shows that reduction of the entropic cost of bringing together the reactants along with a geometric destabilization of the reactant supercomplex are the major contributors to the rate acceleration compared to the background reaction. Finally, a sensitivity analysis is conducted to assess the stability of the results with respect to the choice of methodology.

  • 19.
    Engelmark Cassimjee, Karim
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Manta, Bianca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    A quantum chemical study of the ω-transaminase reaction mechanism2015Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, nr 31, s. 8453-8464Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ω-Transaminases are valuable tools in biocatalysis due to their stereospecificity and their broad substrate range. In the present study, the reaction mechanism of Chromobacterium violaceum ω-transaminase is investigated by means of density functional theory calculations. A large active site model is designed based on the recent X-ray crystal structure. The detailed energy profile for the half-transamination of (S)-1-phenylethylamine to acetophenone is calculated and the involved transition states and intermediates are characterized. The model suggests that the amino substrate forms an external aldimine with the coenzyme pyridoxal-5′-phosphate (PLP), through geminal diamine intermediates. The external aldimine is then deprotonated in the rate-determining step, forming a planar quinonoid intermediate. A ketimine is then formed, after which a hemiaminal is produced by the addition of water. Subsequently, the ketone product is obtained together with pyridoxamine-5′-phosphate (PMP). In the studied half-transamination reaction the ketone product is kinetically favored. The mechanism presented here will be valuable to enhance rational and semi-rational design of engineered enzyme variants in the development of ω-transaminase chemistry.

  • 20. Ertem, Mehmed Z.
    et al.
    Cramer, Christopher J.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    N-O bond cleavage mechanism(s) in nitrous oxide reductase2012Inngår i: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 17, nr 5, s. 687-698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Quantum chemical calculations of active-site models of nitrous oxide reductase (N2OR) have been undertaken to elucidate the mechanism of N-O bond cleavage mediated by the supported tetranuclear Cu4S core (Cu-Z) found in the enzymatic active site. Using either a minimal model previously employed by Gorelsky et al. (J. Am. Chem. Soc. 128:278-290, 2006) or a more extended model including key residue side chains in the active-site second shell, we found two distinct mechanisms. In the first model, N2O binds to the fully reduced Cu-Z in a bent mu-(1,3)-O,N bridging fashion between the Cu-I and Cu-IV centers and subsequently extrudes N-2 while generating the corresponding bridged mu-oxo species. In the second model, substrate N2O binds loosely to one of the coppers of Cu-Z in a terminal fashion, i.e., using only the oxygen atom; loss of N-2 generates the same mu-oxo copper core. The free energies of activation predicted for these two alternative pathways are sufficiently close to one another that theory does not provide decisive support for one over the other, posing an interesting problem with respect to experiments that might be designed to distinguish between the two. Effects of nearby residues and active-site water molecules are also explored.

  • 21.
    Georgieva, Polina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Quantum chemical modeling of enzymatic reactions: The Case of histone lysine methyltransferase2010Inngår i: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 31, nr 8, s. 1707-1714Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 22. Georgieva, Polina
    et al.
    Wu, Qian
    McLeish, Michael J.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    The reaction mechanism of phenylethanolamine N-methyltransferase: A density functional theory study2009Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1794, nr 12, s. 1831-1837Artikkel i tidsskrift (Fagfellevurdert)
  • 23. Ghobril, Cynthia
    et al.
    Hammar, Peter
    Kodepelly, Sanjeevarao
    Spiess, Bernard
    Wagner, Alain
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Baati, Rachid
    Structure-Reactivity Relationship Studies for Guanidine-Organocatalyzed Direct Intramolecular Aldolization of Ketoaldehydes2010Inngår i: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 2, nr 12, s. 1573-1581Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Structure-reactivity studies are performed to explore the reaction mechanism of the guanidine-catalyzed intramolecular aldol reaction of ketoaldehydes. A large number of guanidine and guanidine-like catalysts are synthesized and their properties studied. Kinetic profiles and pK(a) values of the catalysts are measured and correlated to reaction barriers calculated using density functional theory (DFT). The DFT calculations show that structural rigidity influences the pKa of the guanidines. Although the basicity is a very important factor in the catalysis, it is not sufficient to fully account for its catalytic efficiency. The availability of two aligned nitrogen reaction sites for proton shuttling in the transition state is an essential feature that helps to rationalize the reactivity pattern and the activation mode for this family of organocatalysts.

  • 24.
    Goncalves, Sylvie
    et al.
    Universite de Strasbourg, Faculte de Pharmacie UMR/CNRS 7199, Laboratoire des Systemes Chimiques Fonctionnels, Illkirch, France.
    Santoro, Stefano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nicolas, Marc
    Les Laboratoires Pierre Fabre, Centre de Developpement Chimique et Industriel, Gaillac, France.
    Wagner, Alain
    Universite de Strasbourg, Faculte de Pharmacie UMR/CNRS 7199, Laboratoire des Systemes Chimiques Fonctionnels, Illkirch, France.
    Maillos, Philippe
    Les Laboratoires Pierre Fabre, Centre de Developpement Chimique et Industriel, Gaillac, France.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Baati, Rachid
    Universite de Strasbourg, Faculte de Pharmacie UMR/CNRS 7199, Laboratoire des Systemes Chimiques Fonctionnels, Illkirch, France.
    Cationic cyclization of 2-alkenyl-1,3-dithiolanes: DiastereoselectiveSynthesis of trans-decalins2011Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, nr 9, s. 3274-3285Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An unprecedented and highly diastereoselective 6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has beendeveloped yielding trans-decalins, an important scaffold present in numerous di- and triterpenes. The novelty of this 6-endo-trigc yclization stands in the stepwise mechanism involving 2-alkenyl-1,3-dithiolane, acting as a novel latent initiator. It is suggested that the thioketal opens temporarily under the influence of TMSOTf, triggering the cationic 6-endo-trig cyclization, andcloses after C−C bond formation and diastereoselective protonation to terminate the process. DFT calculations confirm this mechanistic proposal and provide a rationale for the observed diastereoselectivity. The reaction tolerates a wide range of functionalities and nucleophilic partners within the substrate. We have also shown that the one-pot 6-endo-trig cyclization followedby in situ 1,3-dithiolane deprotection afford directly the corresponding ketone. This improvement allowed the achievement of the shortest total synthesis of triptophenolide and the shortest formal synthesis of triptolide.

  • 25.
    Gudmundsson, Arnar
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Gustafson, Karl P. J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yang, Bin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed Cycloisomerization of alpha-Allenols2018Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, nr 1, s. 12-16Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Herein, we report a highly efficient iron-catalyzed intramolecular nucleophilic cyclization of alpha-allenols to furnish substituted 2,3-dihydrofurans under mild reaction conditions. A highly diastereoselective variant of the reaction was developed as well, giving diastereomeric ratios of up to 98:2. The combination of the iron-catalyzed cycloisomerization with enzymatic resolution afforded the 2,3-dihydrofuran in high ee. A detailed DFT study provides insight into the reaction mechanism and gives a rationalization for the high chemo-and diastereoselectivity.

  • 26.
    Guðmundsson, Arnar
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Gustafson, Karl P. J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Khanh Mai, Binh
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Hobiger, Viola
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yang, Bin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Iron Catalyzed Cyclization of N-protected a-Allenic Amines to 2,3-dihydropyrrolesManuskript (preprint) (Annet vitenskapelig)
  • 27. Hayashi, Yukiko
    et al.
    Santoro, Stefano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Azuma, Yuki
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ohshima, Takashi
    Mashima, Kazushi
    Enzyme-Like Catalysis via Ternary Complex Mechanism: Alkoxy-Bridged Dinuclear Cobalt Complex Mediates Chemoselective O-Esterification over N-Amidation2013Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 135, nr 16, s. 6192-6199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hydroxy group-selective acylation in the presence of more nucleophilic amines was achieved using acetates of first-row late transition metals, such as Mn, Fe, Co, Cu, and Zn. Among them, cobalt(II) acetate was the best catalyst in terms of reactivity and selectivity. The combination of an octanuclear cobalt carboxylate cluster [Co-4(OCOR)(6)O](2) (2a: R = CF3, 2b: R = CH3, 2c: R = Bu-t) with nitrogen-containing ligands, such as 2,2'-bipyridine, provided an efficient catalytic system for transesterification, in which an alkoxide-bridged dinuclear complex, Co-2((OCOBu)-Bu-t)(2)-(bpy)(2)(mu(2)-OCH2-C6H4-4-CH3)(2) (10), was successfully isolated as a key intermediate. Kinetic studies and density functional theory calculations revealed Michaelis-Menten behavior of the complex 10 through an ordered ternary complex mechanism similar to dinuclear metallo-enzymes, suggesting the formation of alkoxides followed by coordination of the ester.

  • 28.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Recent Trends in Quantum Chemical Modeling of Enzymatic Reactions2017Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, nr 20, s. 6780-6786Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The quantum chemical cluster approach is a powerful method for investigating enzymatic reactions. Over the past two decades, a large number of highly diverse systems have been studied and a great wealth of mechanistic insight has been developed using this technique. This Perspective reviews the current status of the methodology. The latest technical developments are highlighted, and challenges are discussed. Some recent applications are presented to illustrate the capabilities and progress of this approach, and likely future directions are outlined.

  • 29. Huang, Genping
    et al.
    Diner, Colin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism and Stereoselectivity of the BINOL-Catalyzed Allylboration of Skatoles2017Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, nr 21, s. 5904-5907Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Density functional theory calculations have been performed to investigate the binaphthol-catalyzed allylboration of skatoles. The high stereoselectivity observed for the reaction is reproduced well by the calculations and was found to be mainly a result of steric repulsions in the corresponding Zimmerman-Traxler transition states. The role of the additive MeOH in enhancing the stereoselectivity was also investigated and is suggested to promote the formation of less reactive allylboronic ester intermediates, thereby suppressing the formation of allylboroxine species, which undergo the facile racemic background reaction.

  • 30.
    Huang, Genping
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism and Selectivity of Rhodium-Catalyzed 1:2 Coupling of Aldehydes and Allenes2013Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 135, nr 20, s. 7647-7659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The rhodium-catalyzed highly regioselective 1:2 coupling of aldehydes and allenes was investigated by means of density functional theory calculations. Full free energy profiles were calculated, and several possible reaction pathways were evaluated. It is shown that the energetically most plausible catalytic cycle is initiated by oxidative coupling of the two allenes, which was found to be the rate-determining step of the overall reaction. Importantly, Rh allyl complexes that are able to adopt both eta(3) and eta(1) configurations were identified as key intermediates present throughout the catalytic cycle with profound implications for the selectivity of the reaction. The calculations reproduced and rationalized the experimentally observed selectivities and provided an explanation for the remarkable alteration in the product distribution when the catalyst precursor is changed from [RhCl(nbd)](2) (nbd = norbornadiene) to complexes containing noncoordinating counterions ([Rh(cod)(2)X]; X = OTf, BF4, PF6; cod = 1,5-cyclooctadiene). It turns out that the overall selectivity of the reaction is controlled by a combination of the inherent selectivities of several of the elementary steps and that both the mechanism and the nature of the selectivity-determining steps change when the catalyst is changed.

  • 31.
    Huang, Genping
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Liao, Rong-Zhen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism, reactivity, and selectivity of the iridium-catalyzed C(sp(3))-H borylation of chlorosilanes2015Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 6, nr 3, s. 1735-1746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The iridium-catalyzed C(sp(3))-H borylation of methylchlorosilanes is investigated by means of density functional theory, using the B3LYP and M06 functionals. The calculations establish that the resting state of the catalyst is a seven-coordinate Ir(V) species that has to be converted into an Ir(III)tris(boryl) complex in order to effect the oxidative addition of the C-H bond. This is then followed by a C-B reductive elimination to yield the borylated product, and the catalytic cycle is finally completed by the regeneration of the active catalyst over two facile steps. The two employed functionals give somewhat different conclusions concerning the nature of the rate-determining step, and whether reductive elimination occurs directly or after a prior isomerization of the Ir(V) hydride intermediate complex. The calculations reproduce quite well the experimentally-observed trends in the reactivities of substrates with different substituents. It is demonstrated that the reactivity can be correlated to the Ir-C bond dissociation energies of the corresponding Ir(V) hydride intermediates. The effect of the chlorosilyl group is identified to originate from the alpha-carbanion-stabilizing effect of the silicon, which is further reinforced by the presence of an electron-withdrawing chlorine substituent. Furthermore, the source of selectivity for the borylation of primary over secondary C(sp(3))-H can be explained on a steric basis, by repulsion between the alkyl group and the Ir/ligand moiety. Finally, the difference in the reactivity between C(sp(3))-H and C(sp(2))-H borylation is investigated and rationalized in terms of distortion/interaction analysis.

  • 32. Ibrahem, Ismail
    et al.
    Santoro, Stefano
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Córdova, Armando
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Enantioselective conjugate silyl additions to α,β-unsaturated aldehydes catalyzed by combination of transition metal and chiral amine catalysts2011Inngår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 353, nr 2+3, s. 245-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report that transition metal-catalyzed nucleophilic activation can be combined with chiral amine-catalyzed iminium activation as exemplified by the unprecedented enantioselective conjugate addition of a dimethylsilanyl group to α,β-unsaturated aldehydes. These reactions proceed with excellent 1,4-selectivity to afford the corresponding β-silyl aldehyde products 3 in high yields and up to 97:3 er using inexpensive bench stable copper salts and simple chiral amine catalysts. The reaction canalso generate a quaternary stereocenter with goodenantioselectivity. Density functional calculations are performed to elucidate the reaction mechanism and the origin of enantioselectivity.

  • 33.
    Jalilian, Ehsan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Liao, Rong-Zhen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Brismar, Hjalmar
    Laurell, Fredrik
    Lidin, Sven
    Luminescence properties of the Cu4I62- cluster2011Inngår i: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 13, nr 14, s. 4729-4734Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two new solvates were prepared in the system Cu(I)I using a solvolysis reaction. The structures for both of them were solved by X-ray crystllaography, showing that they constitute two modifications of the same compound with the net formula [Cu4I6](P(C6H5)4)2·2OC(CH3)2. Both types of crystals show vivid fluorescence when exposed to UV light. The formation of the first modification (I) seems to be preferred by kinetics and on ageing in the mother liquor it converts to modification (II). The Cu positions in (I) are disordered while those in (II) are fully ordered. The luminescent properties of both crystals were characterized using a confocal microscope and an excitation wavelength of 405 nm, resulting in fluorescence spectra with the intensities of 1.22 and 0.52 relative to the reference (fluorescein 10 µM). Density functional theory calculations on the ordered Cu4I62− core of modification (II) show that the de-excitation from LUMO to HOMO is responsible for the luminescence. The calculated emission spectrum has a maximum at 531 nm in good agreement with the results from confocal microscopy.

  • 34.
    Jalilian, Ehsan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Liao, Rong-Zhen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lidin, Sven
    Luminescence properties of monoclinic Cu4I4(Piperidine)42011Inngår i: Materials research bulletin, ISSN 0025-5408, E-ISSN 1873-4227, Vol. 46, nr 8, s. 1192-1196Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A new modification of Cu4I4Pip4 has been synthesized under hydrothermal conditions. X-ray crystallography revealed that this compound crystallized in the monoclinic system and consists of a tetrahedral core with composition Cu4I4, in which each Cu atom is coordinated by a piperidine molecule via the N atom. In contrast to a previously reported modification of Cu4I4Pip4, the present modification shows luminescent properties when exposed to UV-light. In addition, we have used time-dependent density functional theory calculations to characterize both compounds in term of both absorption and emission.

  • 35.
    Jimenez-Halla, J. Oscar C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stawinski, Jacek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Computational study of the mechanism and selectivity of palladium catalyzed propargylic substitution with phosphorus nucleophiles2012Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 39, s. 12424-12436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mechanism and sources of selectivity in the palladium-catalyzed propargylic substitution reaction that involves phosphorus nucleophiles, and which yields predominantly allenylphosphonates and related compounds, have been studied computationally by means of density functional theory. Full free-energy profiles are computed for both H-phosphonate and H-phosphonothioate substrates. The calculations show that the special behavior of H-phosphonates among other heteroatom nucleophiles is indeed reflected in higher energy barriers for the attack on the central carbon atom of the allenyl/propargyl ligand relative to the ligand-exchange pathway, which leads to the experimentally observed products. It is argued that, to explain the preference of allenyl- versus propargyl-phosphonate/phosphonothioate formation in reactions that involve H-phosphonates and H-phosphonothioates, analysis of the complete free-energy surfaces is necessary, because the product ratio is determined by different transition states in the respective branches of the catalytic cycle. In addition, these transition states change in going from a H-phosphonate to a H-phosphonothioate nucleophile.

  • 36.
    Kalek, Marcin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Combining Meyer-Schuster Rearrangement with Aldol and Mannich Reactions: Theoretical Study of the Intermediate Interception Strategy2012Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, nr 46, s. 19159-19169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Interception of the transient allenyl enolate intermediate of the vanadium-catalyzed Meyer-Schuster rearrangement with aldehydes and imines has been studied computationally using density functional theory. Mechanistic details of the catalytic cycles for each of the reaction variants are established. In particular, it is shown that the active form of I the catalyst contains two triphenylsiloxy ligands, the transesterification of vanadate occurs via sigma-bond metathesis, and vanadium enolate is directly involved in the key C-C bond formation. The calculations also provide support for the dissociative course of the key 1,3-shift step. The stereochemistry of the reaction is thoroughly investigated, and the obtained energy barriers reproduce and rationalize the experimentally observed (Z)-, (E)-selectivity. The calculated free energy profiles are analyzed in terms of efficiency of the intermediate enolate interception. It is shown that the investigated reactions represent borderline cases, in which the intermediate trapping is only slightly favored over the undesired isomerization pathway.

  • 37. Kalek, Marcin
    et al.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism and Selectivity of Cooperatively Catalyzed Meyer-Schuster Rearrangement/Tsuji-Trost Allylic Substitution. Evaluation of Synergistic Catalysis by Means of Combined DFT and Kinetics Simulations2017Inngår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, nr 30, s. 10250-10266Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reaction between propargylic alcohols and allylic carbonates, engaging vanadium and palladium catalysts, is an exemplary case of a cooperatively catalyzed process. This combined Meyer-Schuster rearrangement/Tsuji-Trost allylic substitution clearly illustrates the enormous advantages offered by the simultaneous use of two catalysts, but also the inherent challenges regarding selectivity associated with such a reaction design. These challenges originate from the fact that the desired product of the combined process is formed by a bimolecular coupling of the two substrates activated by the respective catalysts. However, these two processes may also occur in a detached way via the reactions of the catalytic intermediates with the starting propargylic alcohol present in the reaction mixture, leading to the formation of two side-products. Herein, we investigate the overall mechanism of this reaction using density functional theory (DFT) methodology. The mechanistic details of the catalytic cycles for all the individual processes are established. In particular, it is shown that the diphosphine ligand, dppm, used in the reaction promotes the formation of dinuclear palladium complexes, wherein only a single metal center is directly involved in the catalysis. Due to the complexity of the combined reaction network, kinetics simulation techniques are employed in order to analyze the overall selectivity. The simulations directly link the results of the DFT calculations with the experimental data and confirm that the computed free energy profiles indeed reproduce the observed selectivities. In addition, a sensitivity analysis is carried out to assess the importance of the individual steps on the product distribution. The observed behavior of the kinetic network is rationalized, and trends in the reaction outcome upon changing the initial conditions, such as the catalysts amounts and ratio, are discussed. The results provide a general framework for understanding the factors governing the selectivity of the cooperatively catalyzed reactions.

  • 38. Kazemi, Masoud
    et al.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Aqvist, Johan
    Peptide Release on the Ribosome Involves Substrate-Assisted Base Catalysis2016Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 6, nr 12, s. 8432-8439Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Termination of protein synthesis on the ribosome involves hydrolysis of the ester bond between the P-site tRNA and the nascent peptide chain. This reaction occurs in the peptidyl transferase center and is triggered by the class I release factors RF1 and RF2 in prokaryotes. Peptidyl-tRNA hydrolysis is pH-dependent, and experimental results suggest that an ionizable group with pK(a) > 9 is involved in the reaction. The nature of this group is, however, unknown. To resolve this problem, we conducted density functional theory calculations using a large cluster model of the peptidyl transferase center. Our calculations reveal that peptidyl-tRNA hydrolysis occurs via a base-catalyzed mechanism with a predicted activation energy of 15.8 kcal mol(-1), which is in good agreement with experimental data. In this mechanism, the P-site A76 2'-OH group is deprotonated and acts as the general base by activating the nucleophilic water molecule. The energy cost of deprotonating the 2'-hydroxyl group at pH 7.5 is estimated to be about 8 kcal mo1(-1), on the basis of its experimental plc in aqueous solution, and this step is predicted to be the source of the observed pH dependence. The proposed mechanism is consistent not only with experimentally derived activation energies but also with the observed kinetic solvent isotope effect.

  • 39. Kazemi, Masoud
    et al.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Åqvist, Johan
    Enzyme catalysis by entropy without Circe effect2016Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 9, s. 2406-2411Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Entropic effects have often been invoked to explain the extraordinary catalytic power of enzymes. In particular, the hypothesis that enzymes can use part of the substrate-binding free energy to reduce the entropic penalty associated with the subsequent chemical transformation has been very influential. The enzymatic reaction of cytidine deaminase appears to be a distinct example. Here, substrate binding is associated with a significant entropy loss that closely matches the activation entropy penalty for the uncatalyzed reaction inwater, whereas the activation entropy for the rate-limiting catalytic step in the enzyme is close to zero. Herein, we report extensive computer simulations of the cytidine deaminase reaction and its temperature dependence. The energetics of the catalytic reaction is first evaluated by density functional theory calculations. These results are then used to parametrize an empirical valence bond description of the reaction, which allows efficient sampling by molecular dynamics simulations and computation of Arrhenius plots. The thermodynamic activation parameters calculated by this approach are in excellent agreement with experimental data and indeed show an activation entropy close to zero for the rate-limiting transition state. However, the origin of this effect is a change of reaction mechanism compared the uncatalyzed reaction. The enzyme operates by hydroxide ion attack, which is intrinsically associated with a favorable activation entropy. Hence, this has little to do with utilization of binding free energy to pay the entropic penalty but rather reflects how a preorganized active site can stabilize a reaction path that is not operational in solution.

  • 40.
    Kazemi, Masoud
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Uppsala University, Sweden.
    Socan, Jaka
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Åqvist, Johan
    Mechanistic alternatives for peptide bond formation on the ribosome2018Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 11, s. 5345-5354Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The peptidyl transfer reaction on the large ribosomal subunit depends on the protonation state of the amine nucleophile and exhibits a large kinetic solvent isotope effect (KSIE similar to 8). In contrast, the related peptidyl-tRNA hydrolysis reaction involved in termination shows a KSIE of similar to 4 and a pH-rate profile indicative of base catalysis. It is, however, unclear why these reactions should proceed with different mechanisms, as the experimental data suggests. One explanation is that two competing mechanisms may be operational in the peptidyl transferase center (PTC). Herein, we explored this possibility by re-examining the previously proposed proton shuttle mechanism and testing the feasibility of general base catalysis also for peptide bond formation. We employed a large cluster model of the active site and different reaction mechanisms were evaluated by density functional theory calculations. In these calculations, the proton shuttle and general base mechanisms both yield activation energies comparable to the experimental values. However, only the proton shuttle mechanism is found to be consistent with the experimentally observed pH-rate profile and the KSIE. This suggests that the PTC promotes the proton shuttle mechanism for peptide bond formation, while prohibiting general base catalysis, although the detailed mechanism by which general base catalysis is excluded remains unclear.

  • 41.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Georgieva, Polina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism of mycolic acid cyclopropane synthase: A theoretical study2011Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 50, nr 9, s. 1505-1513Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reaction mechanism of mycolic acid cyclopropane synthase is investigated using hybrid density functional theory. The direct methylation mechanism is examined with a large model of the active site constructed on the basis of the crystal structure of the native enzyme. The important active site residue Glu140 is modeled in both ionized and neutral forms. We demonstrate that the reaction starts via the transfer of a methyl to the substrate double bond, followed by the transfer of a proton from the methyl cation to the bicarbonate present in the active site. The first step is calculated to be rate-limiting, in agreement with experimental kinetic results. The protonation state of Glu140 has a rather weak influence on the reaction energetics. In addition to the natural reaction, a possible side reaction, namely a carbocation rearrangement, is also considered and is shown to have a low barrier. Finally, the energetics for the sulfur ylide proposal, which has already been ruled out, is also estimated, showing a large energetic penalty for ylide formation.

  • 42.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Theoretical study of the chemoselectivity of tungsten-dependent acetylene hydratase2011Inngår i: ACS Catalysis, ISSN 2155-5435, Vol. 1, nr 8, s. 937-944Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tungsten-dependent enzyme acetylene hydratase catalyzes the hydration of acetylene to acetaldehyde. Very recently, we proposed a reaction mechanism for this enzyme based on density functional calculations (Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 22523). The mechanism involves direct coordination of the substrate to the tungsten ion, followed by a nucleophilic attack by a water molecule concerted with a proton transfer to a second-shell aspartate, which then reprotonates the substrate. Here, we use the same methodology to investigate the factors involved in the control of the chemoselectivity of this enzyme. The hydration reactions of three representative compounds (propyne, ethylene, and acetonitrile) are investigated using a large model of the active site. The energy of substrate binding to the metal ion and the barrier for the following nucleophilic attack are used to rationalize the experimental observations. It is shown that all three compounds have higher barriers for hydration compared with acetylene. In addition, propyne is shown to have a larger binding energy, explaining its behavior as a competitive inhibitor. Taken together, the results provide further corroboration of our suggested mechanism for acetylene hydratase

  • 43.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Liu, Ruo-Zhuang
    Dipeptide hydrolysis by the dinuclear zinc enzyme human renal dipeptidase: Mechanistic insights from DFT calculations2010Inngår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 104, nr 1, s. 37-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reaction mechanism of the dinuclear zinc enzyme human renal dipeptidase is investigated using hybrid density functional theory. This enzyme catalyzes the hydrolysis of dipeptides and beta-lactam antibiotics. Two different protonation states in which the important active site residue Asp288 is either neutral or ionized were considered. In both cases, the bridging hydroxide is shown to be capable of performing the nucleophilic attack on the substrate carbonyl carbon from its bridging position, resulting in the formation of a tetrahedral intermediate. This step is followed by protonation of the dipeptide nitrogen, coupled with C-N bond cleavage. The calculations establish that both cases have quite feasible energy barriers. When the Asp288 is neutral, the hydrolytic reaction occurs with a large exothermicity. However, the reaction becomes very close to thermoneutral with an ionized Asp288. The two zinc ions are shown to play different roles in the reaction. Zn1 binds the amino group of the substrate, and Zn2 interacts with the carboxylate group of the substrate, helping in orienting it for the nucleophilic attack. In addition, Zn2 stabilizes the oxyanion of the tetrahedral intermediate, thereby facilitating the nucleophilic attack

  • 44.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Liu, Ruo-Zhuang
    Theoretical study of the RNA hydrolysis mechanism of the dinuclear zinc enzyme RNase Z2009Inngår i: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, Vol. 2009, nr 20, s. 2967-2972Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RNase Z is a dinuclear zinc enzyme that catalyzes the removal of the tRNA 3'-end trailer. Density functional theory is used to investigate the phosphodiester hydrolysis mechanism of this enzyme with a model of the active site constructed on the basis of the crystal structure. The calculations imply that the reaction proceeds through two steps. The first step is a nucleophihc attack by a bridging hydroxide coupled with protonation of the leaving group by a Glu-His diad. Subsequently, a water molecule activated by the same Glu-His diad makes a reverse attack, regenerating the bridging hydroxide. The second step is calculated to be the rate-limiting step with a barrier of 18 kcal/mol, in good agreement with experimental kinetic studies. Both zinc ions participate in substrate binding and orientation, facilitating nucleophilic attack. In addition, they act as electrophilic catalysts to stabilize the pentacoordinate trigonal-bipyramidal transition states.

  • 45. Liao, Rong-Zhen
    et al.
    Santoro, Stefano
    Gotsev, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Marcelli, Tommaso
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Origins of Stereoselectivity in Peptide-Catalyzed Kinetic Resolution of Alcohols2016Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 6, nr 2, s. 1165-1171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The origin of the stereoselectivity of the tetrapeptide-catalyzed kinetic resolution of trans-2-N-acetamidocyclohexanol is investigated by means of density functional theory calculations. Transition states for the functionalization of both (R,R) and (S,S) substrates were optimized considering all possible conformers. Due to the flexibility of the peptidic catalyst, a large number of transition states had to be located, and analysis of the geometries and energies allowed for the identification of the main factors that control the stereo selectivity.

  • 46.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism of tungsten-dependent acetylene hydratase from quantum chemical calculations2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 52, s. 22523-22527Artikkel i tidsskrift (Fagfellevurdert)
  • 47.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Phosphate Mono- and Diesterase Activities of the Trinuclear Zinc Enzyme Nuclease P1—Insights from Quantum Chemical Calculations2010Inngår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 49, nr 15, s. 6883-6888Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nuclease P1 is a trinuclear zinc enzyme that catalyzes the hydrolysis of single-stranded DNA and RNA. Density functional calculations are used to elucidate the reaction mechanism of this enzyme with a model of the active site designed on the basis of the X-ray crystal structure. 2-Tetrahydrofuranyl phosphate and methyl 2-tetrahydrofuranyl phosphate substrates are used to explore the phosphomonoesterase and phosphodiesterase activities of this enzyme, respectively. The calculations reveal that for both activities, a bridging hydroxide performs an in-line attack on the phosphorus center, resulting in inversion of the configuration. Simultaneously, the P−O bond is cleaved, and Zn2 stabilizes the negative charge of the leaving alkoxide anion and assists its departure. All three zinc ions, together with Arg48, provide electrostatic stabilization to the penta-coordinated transition state, thereby lowering the reaction barrier.

  • 48.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Quantum chemical modeling of enzymatic reactions: The case of decarboxylation2011Inngår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 07, nr 05, s. 1494-1501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a systematic study of the decarboxylation step of the enzyme aspartate decarboxylase with the purpose of assessing the quantum chemical cluster approach for modeling this important class of decarboxylase enzymes. Active site models ranging in size from 27 to 220 atoms are designed, and the barrier and reaction energy of this step are evaluated. To model the enzyme surrounding, homogeneous polarizable medium techniques are used with several dielectric constants. The main conclusion is that when the active site model reaches a certain size, the solvation effects from the surroundings saturate. Similar results have previously been obtained from systematic studies of other classes of enzymes, suggesting that they are of a quite general nature.

  • 49.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Reaction Mechanism of the Dinuclear Zinc Enzyme N-Acyl-l-homoserine Lactone Hydrolase: A Quantum Chemical Study2009Inngår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 48, nr 4, s. 1442-1448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    N-acyl-L-homosedne 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.

  • 50.
    Liao, Rong-Zhen
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yu, Jian-Guo
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Reaction Mechanism of the Trinuclear Zinc Enzyme Phospholipase C: A Density Functional Theory Study2010Inngår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, nr 7, s. 2533-2540Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phosphatidylcholine-preferring phospholipase C is a trinuclear zinc-dependent phosphodiesterase, catalyzing the hydrolysis of choline phospholipids. In the present study, density functional theory is used to investigate the reaction mechanism of this enzyme. Two possible mechanistic scenarios were considered with a model of the active site designed on the basis of the high resolution X-ray crystal structure of the native enzyme. The calculations show that a Zn1 and Zn3 bridging hydroxide rather than a Zn1 coordinated water molecule performs the nucleophilic attack on the phosphorus center. Simultaneously, Zn2 activates a water molecule to protonate the leaving group. In the following step, the newly generated Zn2 bound hydroxide makes the reverse attack, resulting in the regeneration of the bridging hydroxide. The first step is calculated to be rate-limiting with a barrier of 17.3 kcal/mol, in good agreement with experimental kinetic studies. The zinc ions are suggested to orient the substrate for nucleophilic attack and provide electrostatic stabilization to the dianionic penta-coordinated trigonal bipyramidal transition states, thereby lowering the barrier.

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