| 1. |
- Duarte, Fernanda, et al.
(författare)
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Concerted or Stepwise : How Much Do Free-Energy Landscapes Tell Us about the Mechanisms of Elimination Reactions?
- 2014
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:3, s. 1280-1288
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Tidskriftsartikel (refereegranskat)abstract
- The base-catalyzed dehydration of benzene cis-1,2-dihydrodiols is driven by formation of an aromatic product as well as intermediates potentially stabilized by hyperaromaticity. Experiments exhibit surprising shifts in isotope effects, indicating an unusual mechanistic balance on the E2-E1cB continuum. In this study, both land 2-dimensional free energy surfaces are generated for these compounds with various substituents, using density functional theory and a mixed implicit/explicit solvation model. The computational data help unravel hidden intermediates along the reaction coordinate and provide a novel conceptual framework for distinguishing between competing pathways in this and any other system with borderline reaction mechanisms.
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| 2. |
- Duarte, Fernanda, et al.
(författare)
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Force Field Independent Metal Parameters Using a Nonbonded Dummy Model
- 2014
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 118:16, s. 4351-4362
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Tidskriftsartikel (refereegranskat)abstract
- The cationic dummy atom approach provides a powerful nonbonded description for a range of alkaline-earth and transition-metal centers, capturing both structural and electrostatic effects. In this work we refine existing literature parameters for octahedrally coordinated Mn2+, Zn2+, Mg2+, and Ca2+, as well as providing new parameters for Ni2+, Co2+, and Fe2+. In all the cases, we are able to reproduce both M2+-O distances and experimental solvation free energies, which has not been achieved to date for transition metals using any other model. The parameters have also been tested using two different water models and show consistent performance. Therefore, our parameters are easily transferable to any force field that describes nonbonded interactions using Coulomb and Lennard-Jones potentials. Finally, we demonstrate the stability of our parameters in both the human and Escherichia coli variants of the enzyme glyoxalase 1 as showcase systems, as both enzymes are active with a range of transition metals. The parameters presented in this work provide a valuable resource for the molecular simulation community, as they extend the range of metal ions that can be studied using classical approaches, while also providing a starting point for subsequent parametrization of new metal centers.
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| 3. |
- Duarte, Fernanda, et al.
(författare)
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The Alkaline Hydrolysis of Sulfonate Esters : Challenges in Interpreting Experimental and Theoretical Data
- 2014
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:7, s. 2816-2828
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Tidskriftsartikel (refereegranskat)abstract
- Sulfonate ester hydrolysis has been the subject of recent debate, with experimental evidence interpreted in terms of both stepwise and concerted mechanisms. In particular, a recent study of the alkaline hydrolysis of a series of benzene arylsulfonates (Babtie et al., Org. Biomol. Chem. 10, 2012, 8095) presented a nonlinear Bronsted plot, which was explained in terms of a change from a stepwise mechanism involving a pentavalent intermediate for poorer leaving groups to a fully concerted mechanism for good leaving groups and supported by a theoretical study. In the present work, we have performed a detailed computational study of the hydrolysis of these compounds and find no computational evidence for a thermodynamically stable intermediate for any of these compounds. Additionally, we have extended the experimental data to include pyridine-3-yl benzene sulfonate and its N-oxide and N-methylpyridinium derivatives. Inclusion of these compounds converts the Bronsted plot to a moderately scattered but linear correlation and gives a very good Hammett correlation. These data suggest a concerted pathway for this reaction that proceeds via an early transition state with little bond cleavage to the leaving group, highlighting the care that needs to be taken with the interpretation of experimental and especially theoretical data.
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| 4. |
- Repic, Matej, et al.
(författare)
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Empirical valence bond simulations of the hydride transfer step in the monoamine oxidase B catalyzed metabolism of dopamine
- 2014
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 82:12, s. 3347-3355
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Tidskriftsartikel (refereegranskat)abstract
- Monoamine oxidases (MAOs) A and B are flavoenzymes responsible for the metabolism of biogenic amines such as dopamine, serotonin and noradrenaline. In this work, we present a comprehensive study of the rate-limiting step of dopamine degradation by MAO B, which consists in the hydride transfer from the methylene group of the substrate to the flavin moiety of the FAD prosthetic group. This article builds on our previous quantum chemical study of the same reaction using a cluster model (Vianello et al., Eur J Org Chem 2012; 7057), but now considering the full dimensionality of the hydrated enzyme with extensive configurational sampling. We show that MAO B is specifically tuned to catalyze the hydride transfer step from the substrate to the flavin moiety of the FAD prosthetic group and that it lowers the activation barrier by 12.3 kcal mol(-1) compared to the same reaction in aqueous solution, a rate enhancement of more than nine orders of magnitude. Taking into account the deprotonation of the substrate prior to the hydride transfer reaction, the activation barrier in the enzyme is calculated to be 16.1 kcal mol(-1), in excellent agreement with the experimental value of 16.5 kcal mol(-1). Additionally, we demonstrate that the protonation state of the active site residue Lys296 does not have an influence on the hydride transfer reaction.
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| 5. |
- Tirel, Emmanuel Y., et al.
(författare)
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Catalytic Zinc Complexes for Phosphate Diester Hydrolysis
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 53:31, s. 8246-8250
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Tidskriftsartikel (refereegranskat)abstract
- Creating efficient artificial catalysts that can compete with biocatalysis has been an enduring challenge which has yet to be met. Reported herein is the synthesis and characterization of a series of zinc complexes designed to catalyze the hydrolysis of phosphate diesters. By introducing a hydrated aldehyde into the ligand we achieve turnover for DNA-like substrates which, combined with ligand methylation, increases reactivity by two orders of magnitude. In contrast to current orthodoxy and mechanistic explanations, we propose a mechanism where the nucleophile is not coordinated to the metal ion, but involves a tautomer with a more effective Lewis acid and more reactive nucleophile. This data suggests a new strategy for creating more efficient metal ion based catalysts, and highlights a possible mode of action for metalloenzymes.
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