Addition of the Lewis acid Zn(2+) to (TBP(8)Cz)Mn(V)(O) induces valence tautomerization, resulting in the formation of [(TBP(8)Cz(+•))Mn(IV)(O)-Zn(2+)]. This new species was characterized by UV-vis, EPR, the Evans method, and (1)H NMR and supported by DFT calculations. Removal of Zn(2+) quantitatively restores the starting material. Electron-transfer and hydrogen-atom-transfer reactions are strongly influenced by the presence of Zn(2+).
"Although these QM-cluster calculations in many cases were able to reproduce experimentally determined product distributions, kinetic isotope effects and rate constants as well as spectroscopic features of key stable intermediates (Kumar et al., 2005; Vardhaman et al., 2011, 2013a,b), we cannot be certain that the methodology will also work on an enzyme such as a cysteine protease. In particular, QM/MM studies on these enzymatic systems showed that in many cases the active features were sufficient to describe the enzyme accurately (Godfrey et al., 2008; Porro et al., 2009; Kumar et al., 2011b), but in cases where the active species has close lying electronic states environmental perturbations were shown to change the electronic properties of the reactant and consequently the reactivity patterns (Ogliaro et al., 2000; de Visser et al., 2002; Leeladee et al., 2012). We anticipated similar problems in the current system, where strong polar interactions influenced the reaction kinetics, therefore, a combined DFT and QM/MM approach was applied. "
[Show abstract][Hide abstract] ABSTRACT: Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism.
Frontiers in Chemistry 12/2013; 1:39. DOI:10.3389/fchem.2013.00039
[Show abstract][Hide abstract] ABSTRACT: Multiple transition metal functional groups including metaloxo, hydroxo, and hydroperoxide groups play significant roles in various biological and chemical oxidations such as electron transfer, oxygen transfer, and hydrogen abstraction. Further studies that clarify their oxidative relationships and the relationship between their reactivity and their physicochemical properties will expand our ability to predict the reactivity of the intermediate in different oxidative events. As a result researchers will be able to provide rational explanations of poorly understood oxidative phenomena and design selective oxidation catalysts. This Account summarizes results from recent studies of oxidative relationships among manganese(IV) molecules that include pairs of hydroxo/oxo ligands.
Accounts of Chemical Research 11/2012; 46(2). DOI:10.1021/ar300208z · 22.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Redox-inactive metal ions play pivotal roles in regulating reactivities of high-valent metal-oxo species in a variety of enzymatic and chemical reactions. A mononuclear nonheme manganese(IV)-oxo complex bearing a pentadentate N5 ligand has been synthesized and used in the synthesis of a Mn(IV)-oxo complex binding scandium ions. The Mn(IV)-oxo complexes are characterized with various spectroscopic methods. The reactivities of the Mn(IV)-oxo complex are markedly influenced by binding Sc3+ ions in oxidation reactions, such as ~2500-fold increase in the oxidation of thioanisole (i.e., oxygen atom transfer) but ~180-fold decrease in the C-H bond activation of 1,4-cyclohexadiene (i.e., hydrogen atom transfer). The present results provide the first example of a nonheme Mn(IV)-oxo complex binding redox-inactive metal ions that shows a contrasting effect of redox-inactive metal ions on the reactivities of metal-oxo species in the oxygen atom transfer and hydrogen atom transfer reactions.
Journal of the American Chemical Society 01/2013; 135(17). DOI:10.1021/ja312113p · 12.11 Impact Factor
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