| 1. |
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| 2. |
- Alam, Rauful, et al.
(författare)
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Stereoselective allylboration of imines and indoles under mild conditions. An in situ E/Z isomerization of imines by allylboroxines
- 2014
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Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 5:7, s. 2732-2738
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Barbion, Julien, et al.
(författare)
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Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A
- 2012
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 68:32, s. 6504-6512
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
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| 5. |
- Biosca, Maria, et al.
(författare)
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Mechanism of Asymmetric Homologation of Alkenylboronic Acids with CF3-Diazomethane via Borotropic Rearrangement
- 2024
-
Ingår i: Journal of Organic Chemistry. - 0022-3263 .- 1520-6904. ; 89:7, s. 4538-4548
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Tidskriftsartikel (refereegranskat)abstract
- Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF3-diazomethane. The reaction proceeds via a chiral BINOL ester of the alkenylboronic acid substrate. The calculations reveal a complex scenario for the formation of the chiral BINOL-alkenylboronate species, which is the key intermediate in the catalytic process. The aliphatic alcohol additive plays an important role in the reaction. This study provides a rationalization of the stereoinduction step of the reaction, and the enantioselectivity is mainly attributed to the steric repulsion between the CF3 group of the diazomethane reagent and the γ-substituent of the BINOL catalyst. The complex potential energy surface obtained by the calculations is analyzed by means of microkinetic simulations.
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| 6. |
- Biswas, Srijit, et al.
(författare)
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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 Investigation
- 2013
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:52, s. 17939-17950
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
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| 8. |
- Brea, Oriana, et al.
(författare)
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Mechanism(s) of thermal decomposition of N-Nitrosoamides : A density functional theory study
- 2019
-
Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 75:8, s. 929-935
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Tidskriftsartikel (refereegranskat)abstract
- The thermal decomposition of N-nitrosoamides has experimentally been demonstrated to depend on several factors, such as temperature, solvent and the substituents on the substrate. Consequently, a number of reaction mechanisms have been proposed for this process in the literature. In this work, we present a comprehensive computational investigation in which we examine the detailed reaction mechanisms for two N-nitrosoamides (with aliphatic and aromatic substituents) in two different solvents (mesitylene and methanol). It is shown that the reaction mechanism can change dramatically with the nature of the substrate and the choice of solvent. Importantly, it is found that the polar solvent stabilizes ion-pairs that are unstable in the non-polar solvent, which can play a key role in the mechanism.
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| 9. |
- Brea, Oriana, et al.
(författare)
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Mechanisms of Formation and Rearrangement of Benziodoxole-Based CF3 and SCF3 Transfer Reagents
- 2020
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:23, s. 15577-15585
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Tidskriftsartikel (refereegranskat)abstract
- Togni's benziodoxole-based reagents are widely used in trifluoromethylation reactions. It has been established that the kinetically stable hypervalent iodine form (I-CF3) of the reagents is thermodynamically less stable than its acyclic ether isomer (O-CF3). On the other hand, the trifluoromethylthio analogue exists in the thermodynamically stable thioperoxide form (O-SCF3), and the hypervalent form (I-SCF3) has been elusive. Despite the importance of these reagents, very little is known about the reaction mechanisms of their syntheses, which has hampered the development of new reagents of the same family. Herein, we use density functional theory calculations to understand the reasons for the divergent behaviors between the CF3 and SCF3 reagents. We demonstrate that they follow different mechanisms of formation and that the metals involved in the syntheses (potassium in the case of the trifluoromethyl reagent and silver in the trifluoromethylthio analogue) play key roles in the mechanisms and greatly influence the possibility of their rearrangements from the hypervalent (I-CF3, I-SCF3) to the corresponding ether-type form (O-CF3, O-SCF3).
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| 10. |
- Brea, Oriana, et al.
(författare)
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Modeling Decomposition of N-Nitrosoamides in a Self-Assembled Capsule
- 2019
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 84:11, s. 7354-7361
-
Tidskriftsartikel (refereegranskat)abstract
- Density functional theory calculations are employed to investigate the mechanism and energies of the decomposition of N-nitrosoamides in the presence of a resorcinarene-based self-assembled nanocapsule. From experiments, it is known that confinement in the capsule inhibits the thermal decomposition of these compounds. N-Nitrosoamides with both aromatic and aliphatic substituents are considered here and the calculations show that, for both kinds, binding to the capsule leads to a significant increase in the energy barrier of the rate-determining step, the 1,3 N -> O acyl transfer reaction. A distortion-interaction analysis is conducted to probe the reasons behind the inhibition of the reaction. In addition, we characterized hypothetical intermediates that might be involved in the formation of the decomposition products inside the capsule. Interestingly, it is found that the capsule stabilizes ion-pair species that are unstable in mesitylene solution. Finally, a possible explanation is proposed for the observed encapsulation of the decomposition product of only one of the substrates.
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| 11. |
- Bunrit, Anon, et al.
(författare)
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Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
- 2015
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 137:14, s. 4646-4649
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
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| 13. |
- Bunrit, Anon, 1986-, et al.
(författare)
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H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate Heterocycles
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 14. |
- Bunrit, Anon, et al.
(författare)
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Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer
- 2016
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Ingår i: Synlett. - : Georg Thieme Verlag KG. - 0936-5214 .- 1437-2096. ; 27:2, s. 173-176
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 15. |
- Carretero Cerdan, Alba, et al.
(författare)
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Enhancing the chirality transfer in the Isomeri-zation of Electron-deficient Allylic Alcohols.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The study of a confined space for the isomerization of electron-deficient allylic alcohols have been studied. The materials choosen for this purpose are porous materials from commercial avilable polymers to Metal-Organic Frameworks. A derivative of UiO-67 MOF type have been choosen due to its chemical and thermodynamic stability. The heterogeneous material synthesized is robust and it has sligthly improved the chirality transfer in the isomerization of certain allylic alcohols.
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| 16. |
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| 17. |
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| 18. |
- Chen, Shilu, et al.
(författare)
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Peptide Hydrolysis by the Binuclear Zinc Enzyme Aminopeptidase from Aeromonas proteolytica : A Density Functional Theory Study
- 2008
-
Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 112:8, s. 2494-2500
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 19. |
- Chen, Shilu, 1979-
(författare)
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Quantum Chemical Modeling of Binuclear Zinc Enzymes
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the present thesis, the reaction mechanisms of several di-zinc hydrolases have been explored using quantum chemical modeling of the enzyme active sites. The studied enzymes are phosphotriesterase (PTE), aminopeptidase from Aeromonas proteolytica (AAP), glyoxalase II (GlxII), and alkaline phosphatase (AP). All of them contain a binuclear divalent zinc core in the active site. The density functional theory (DFT) method B3LYP functional was employed in the investigations. The potential energy surfaces (PESs) for various reaction pathways have been mapped and the involved transition states and intermediates have been characterized. The hydrolyses of different types of substrates were examined, including phosphate esters (PTE and AP) and the substrates containing carbonyl group (AAP and GlxII). The roles of zinc ions and individual active-site residues were analyzed and general features of di-zinc enzymes have been characterized. The bridging hydroxide stabilized by two zinc ions has been confirmed to be capable of the nucleophile in the hydrolysis reactions. PTE, AAP, and GlxII all employ the bridging hydroxide as the direct nucleophile. Furthermore, it is shown that either one of or both zinc ions provide the main catalytic power by stabilizing the negative charge developing during the reaction and thereby lowering the barriers. In the cases of GlxII and AP, one of zinc ions also contributes to the catalysis by stabilizing the leaving group. These features perfectly satisfy the two requisites for the hydrolysis, i.e. sufficient nucleophilicity and stabilization of charge. A competing mechanism, in which the bridging hydroxide acts as a base, was shown to have significantly higher barrier in the case of PTE. For phosphate hydrolysis reactions, it is important to characterize the nature of the transition states involved in the reactions. Associative mechanisms were observed for both PTE and AP. The former uses a step-wise associative pathway via a penta-coordinated intermediate, while the latter proceeds through a concerted associative path via penta-coordinated transition states. Finally, with PTE as a test case, systematic evaluation of the computational performance of the quantum chemical modeling approach has been performed. This assessment, coupled with other results of this thesis, provide an effective demonstration of the usefulness and powerfulness of quantum chemical active-site modeling in the exploration of enzyme reaction mechanisms and in the characterization of the transition states involved.
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| 20. |
- Chen, Shilu, et al.
(författare)
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Reaction mechanism of the binuclear zinc enzyme glyoxalase II : A theoretical study
- 2009
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 103:2, s. 274-281
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 21. |
- Chen, Shilu, et al.
(författare)
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Technical aspects of quantum chemical modeling of enzymatic reactions : the case of phosphotriesterase
- 2008
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 120:4-6, s. 515-522
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 22. |
- Chen, Shilu, et al.
(författare)
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Theoretical Study of the Phosphotriesterase Reaction Mechanism
- 2007
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 111:6, s. 1253-1255
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 23. |
- Cho, K. B., et al.
(författare)
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The substrate reaction mechanism of class III anaerobic ribonucleotide reductase
- 2001
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1089-5647 .- 1520-6106 .- 1520-5207. ; 105:27, s. 6445-6452
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 24. |
- Chojnacka, Kinga, et al.
(författare)
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Synthetic studies on the solanacol ABC ring system by cation-initiated cascade cyclization : implications for strigolactone biosynthesis
- 2011
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 9:15, s. 5350-5353
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 25. |
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| 26. |
- Cordova, A., et al.
(författare)
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The direct catalytic asymmetric alpha-aminooxylation reaction : Development of stereoselective routes to 1,2-diols and 1,2-amino alcohols and density functional calculations
- 2004
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 10:15, s. 3673-3684
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 27. |
- Das, Biswanath, et al.
(författare)
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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 phosphoesterases
- 2014
-
Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 0162-0134 .- 1873-3344. ; 132, s. 6-17
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 28. |
- Das, Biswanath, et al.
(författare)
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A dinuclear zinc(II) complex of a new unsymmetric ligand with an N5O2 donor set; A structural and functional model for the active site of zinc phosphoesterases.
- 2014
-
Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 132:Online 13 August 2013, s. 6-17
-
Tidskriftsartikel (refereegranskat)abstract
- The dinuclear complex [Zn2(DPCPMP)(pivalate)](ClO4), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin-2-yl)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, [Zn2(DPCPMP)](2+) and [Zn2(DPCPMP)(OH)](+) predominate the solution above pH4. 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 ΔH(‡)=95.6kJmol(-1), ΔS(‡)=-44.8Jmol(-1)K(-1), and ΔG(‡)=108.0kJmol(-1). The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn2(DPCPMP)(μ-OH)](+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFT). Calculations show that the reaction goes through one concerted step (SN2 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.
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| 29. |
- Das, Biswanath, et al.
(författare)
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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 Potato
- 2014
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Ingår i: European Journal of Inorganic Chemistry. - : Wiley. - 1434-1948 .- 1099-1948 .- 1099-0682. ; 2014:13, s. 2204-2212
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 30. |
- Das, Biswanath, et al.
(författare)
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An Unsymmetric Ligand with a N5O2 Donor Set and Its Corresponding Dizinc Complex : A Structural and Functional Phosphoesterase Model
- 2018
-
Ingår i: European Journal of Inorganic Chemistry. - : Wiley. - 1434-1948 .- 1099-1948 .- 1099-0682. ; :36, s. 4004-4013
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 31. |
- Daver, Henrik, et al.
(författare)
-
Mixed Explicit-Implicit Solvation Approach for Modeling of Alkane Complexation in Water-Soluble Self-Assembled Capsules
- 2018
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 140:39, s. 12527-12537
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 32. |
- Daver, Henrik, et al.
(författare)
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Modeling the Reaction of Carboxylic Acids and Isonitriles in a Self-Assembled Capsule
- 2020
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 26:47, s. 10861-10870
-
Tidskriftsartikel (refereegranskat)abstract
- Quantum chemical calculations were used to study the reaction of carboxylic acids with isonitriles inside a resorcinarene-based self-assembled capsule. Experimentally, it has been shown that the reactions betweenp-tolylacetic acid andn-butyl isonitrile or isopropyl isonitrile behave differently in the presence of the capsule compared both with each other and also with their solution counterparts. Herein, the reasons for these divergent behaviors are addressed by comparing the detailed energy profiles for the reactions of the two isonitriles inside and outside the capsule. An energy decomposition analysis was conducted to quantify the different factors affecting the reactivity. The calculations reproduce the experimental findings very well. Thus, encapsulation leads to lowering of the energy barrier for the first step of the reaction, the concerted alpha-addition and proton transfer, which in solution is rate-determining, and this explains the rate acceleration observed in the presence of the capsule. The barrier for the final step of the reaction, the 1,3 O -> N acyl transfer, is calculated to be higher with the isopropyl substituent inside the capsule compared withn-butyl. With the isopropyl substituent, the transition state and the product of this step are significantly shorter than the preceding intermediate, and this results in energetically unfavorable empty spaces inside the capsule, which cause a higher barrier. With then-butyl substituent, on the other hand, the carbon chain can untwine and hence uphold an appropriate guest length.
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| 33. |
- Daver, Henrik, et al.
(författare)
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Quantum Chemical Modeling of Cycloaddition Reaction in a Self-Assembled Capsule
- 2017
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 139:43, s. 15494-15503
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 34. |
- Daver, Henrik, 1984-
(författare)
-
Quantum Chemical Modeling of Phosphoesterase Mimics and Chemistry in Confined Spaces
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next.Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state.In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments.The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein.
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| 35. |
- Daver, Henrik
(författare)
-
Quantum Chemical Modelling of Biomimetic Phosphoesterase Complexes
- 2015
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phosphoesterases are a class of enzymes that catalyze hydrolysis of phosphoester bonds. They facilitate the modification of nucleic acid sequences, as well as the breakdown of rest products of warfare agents and insecticides. In this thesis, three biomimetic complexes that perform the same tasks are studied using density functional theory.Two of the catalysts contain a dizinc core while the third binds an Fe(III) ion and a Mn(II)ion. These complexes catalyze the hydrolysis of the phosphodiester substrate bis-(2,4)-dinitrophenyl phosphate (BDNPP). The substrate is analogous to the phosphoric link between two nucleotides in DNA, and the system is thus a model for cleaving bonds between nucleotides.By means of computational modelling, the reaction mechanisms are investigated in detail. Different binding modes of the substrates to the catalysts are considered and several mechanistic proposals are evaluated. Conclusions are drawn on the basis of free energy barriers calculated for the different mechanisms.In all studied reactions, a hydroxide bridging the metals becomes terminally coordinated to one of the zinc ions and then attacks the phosphorus center in a nucleophilic fashion. Leaving group dissociation takes place without a barrier.One of the catalysts was also studied binding a model substrate for RNA, namely hydroxy-2-isopropyl p-nitrophenyl phosphate (HPNP). The hydroxide was found to act as a base, activating the alcohol moiety of the substrate which in turn performs the nucleophilic attack on the phosphorus center.Common for all studied systems is that the catalyst-product complex is calculated to be the most stable species. Hence, this complex is suggested to be the resting state of the catalytic cycle. The free energy barriers of the reactions are associated with going from the catalystproduct complex of one catalytic cycle to the transition state for nucleophilic attack in the next. Calculated barriers are in good agreements with experiments.
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| 36. |
- Daver, Henrik, et al.
(författare)
-
Theoretical Study of Phosphodiester Hydrolysis and Transesterification Catalyzed by an Unsymmetric Biomimetic Dizinc Complex
- 2016
-
Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 55:4, s. 1872-1882
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 37. |
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| 38. |
- Deliaval, Marie, 1993-
(författare)
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Synthesis of chiral allyl and propargyl boronates by organocatalytic carbene insertion to carbon-boron bonds
- 2023
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the development of a novel organocatalytic method for the synthesis of chiral allyl- and propargyl- organoboron compounds with high enantioselectivity. These organoboron species are versatile building blocks in asymmetric synthesis.We have developed a new efficient homologation method of alkenyl boronic acids. This reaction affords enantiomerically enriched trifluoromethylated allylboronates. These organoboron species were used in allylboration of carbonyl compounds, imines and indole derivatives. The reactions proceeded with a remarkably high stereoselectivity to give homoallylic alcohols and amines. In addition, the chiral allylboronic acids can be oxidized to the corresponding alcohols with retention of the configuration.Based on the homologation of alkenylboronic acids a new three-component reaction is developed. This reaction involved coupling of alkynyl boronates, diazo compounds and ketones in the presence of chiral organocatalysts. This coupling proceeds with high selectivity under mild reaction conditions. The three-component coupling reaction is based on a homologation–allylboration sequence. The process is suitable for synthesis of CF3- and TMS-substituted allenols with excellent diastereo- and enantioselectivity. Application of aromatic, cyclic and non-cyclic ketones leads to formation of chiral tertiary allenols.We have also studied the effects of boronic acid esters on the outcome of the homologation reaction. It was found that a facile transesterification of the boronate precursors with the organocatalyst, BINOL derivatives, is a prerequisite of the successful homologation reaction.
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| 39. |
- Engelmark Cassimjee, Karim, et al.
(författare)
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A quantum chemical study of the ω-transaminase reaction mechanism
- 2015
-
Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:31, s. 8453-8464
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 40. |
- Engstrom, Maria, et al.
(författare)
-
Ab initio g-tensor calculations of the thioether substituted tyrosyl radical in galactose oxidase
- 2000
-
Ingår i: Chemical Physics Letters. - 0009-2614 .- 1873-4448. ; 319:04-mar, s. 191-196
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 41. |
- Engstrom, Maria, et al.
(författare)
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Hydrogen bonding to tyrosyl radical analyzed by ab initio g-tensor calculations
- 2000
-
Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 104:21, s. 5149-5153
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 42. |
- Erdtman, Edvin, 1981-
(författare)
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A theoretical study of 5-Aminolevulinic acid and its esters : properties and lipid permeability
- 2008
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 5-aminolevulinic acid (5ALA) is a widely used prodrug in Photodynamic therapy (PDT). The target molecule in 5ALA-PDT is Protoporphyrin IX (PpIX), which is synthesized endogenously via the heme pathway in the cell. In this thesis; the structural and energetic properties of 5ALA, its methyl-, ethyl- and hexyl esters, four different 5ALA enols, and hydrated 5ALA have been investigated using Quantum Mechanical (QM) first principles calculations. The vacuum proton affinity (PA) of 5ALA is found to be in good agreement with other similar compounds. The keto-enol tautomerization mechanism of 5ALA has been studied, and a self-catalysis mechanism has been proposed to be the most probable. Molecular Dynamics (MD) simulations of a lipid bilayer have been performed to study the membrane permeability of 5ALA and its esters. In the simulations the molecules were inserted in the middle of the membrane, equilibrated, and then simulated in 20 ns. It has been found that there are some differences in penetration between the molecules studied. The methyl ester of 5ALA is diverging from the others by having its barrier not in the middle of the membrane, as the others have.
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| 43. |
- Ertem, Mehmed Z., et al.
(författare)
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N-O bond cleavage mechanism(s) in nitrous oxide reductase
- 2012
-
Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 17:5, s. 687-698
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 44. |
- Georgieva, Polina, et al.
(författare)
-
Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase
- 2008
-
Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614 .- 1873-4448. ; 463:1-3, s. 214-218
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 45. |
- Georgieva, Polina
(författare)
-
Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, quantum chemistry, in particular the B3LYP density functional method, is used to investigate a number of methyl transfer enzymes. Quantum chemical methodology is today a very important tool in the elucidation of properties and reaction mechanisms of enzyme active sites. The enzymes considered in this thesis are the S-adenosyl L-methionine-dependent enzymes - glycine N-methyltransferase, guanidinoacetate methyltransferase, phenylethanolamine N-methyltransferase, and histone lysine methyltransferase. In addition, the reaction mechanism of the DNA repairing enzyme O6-methylguanine methyltransferase is studied. Active site models of varying sizes were designed and stationary points along the reaction paths were optimized and characterized. Potential energy surfaces for the reactions were calculated and the feasibility of the suggested reaction mechanisms was able to be judged. By systematically increasing the size of the models, deeper insight into the details of the reactions was obtained, the roles of the various active site residues could be analyzed, and, very importantly, the adopted modeling strategy was evaluated.
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| 46. |
- Georgieva, Polina, et al.
(författare)
-
Quantum Chemical Modeling of Enzymatic Reactions : The Case of Histone Lysine Methyltransferase
- 2010
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 0192-8651 .- 1096-987X. ; 31:8, s. 1707-1714
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 47. |
- Georgieva, Polina, et al.
(författare)
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The reaction mechanism of phenylethanolamine N-methyltransferase : A density functional theory study
- 2009
-
Ingår i: Biochimica et Biophysica Acta - Proteins and Proteomics. - : Elsevier BV. - 1570-9639 .- 1878-1454. ; 1794:12, s. 1831-1837
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 48. |
- Ghobril, Cynthia, et al.
(författare)
-
Structure and reactivity relationship studies for guanidine-organocatalyzed direct intramolecular aldolization of ketoaldehydes
-
Annan publikation (populärvet., debatt m.m.)abstract
- 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.
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| 49. |
- Ghobril, Cynthia, et al.
(författare)
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Structure-Reactivity Relationship Studies for Guanidine-Organocatalyzed Direct Intramolecular Aldolization of Ketoaldehydes
- 2010
-
Ingår i: ChemCatChem. - : Wiley. - 1867-3880 .- 1867-3899. ; 2:12, s. 1573-1581
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 50. |
- Goncalves, Sylvie, et al.
(författare)
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Cationic cyclization of 2-alkenyl-1,3-dithiolanes: DiastereoselectiveSynthesis of trans-decalins
- 2011
-
Ingår i: Journal of Organic Chemistry. - : American Chemical Society. - 0022-3263 .- 1520-6904. ; 76:9, s. 3274-3285
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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