Gaining Insight into the Catalytic Mechanism of the R132H IDH1 Mutant: A Synergistic DFT Cluster and Experimental Investigation.

Human isocitrate dehydrogenase 1 (IDH1) is an enzyme that is found in humans that plays a critical role in aerobic metabolism. As a part of the citric acid cycle, IDH1 becomes responsible for catalyzing the oxidative decarboxylation of isocitrate to form α-ketoglutarate (αKG), with nicotinamide adenine dinucleotide phosphate (NADP) as a cofactor. Strikingly, mutations of the IDH1 enzyme have been discovered in several cancers including glioblastoma multiforme (GBM), a highly aggressive form of brain cancer.

Computational Insights into the Regeneration of Ovothiol and Ergothioneine and Their Selenium Analogues by Glutathione.

Ovothiol and ergothioneine are powerful antioxidants that readily react with oxidants by forming their respective disulfides. In fact, ovothiol is widely considered one of the most powerful natural antioxidants. However, for these antioxidants to be again involved in reacting with oxidants, they must be regenerated via the reduction of the disulfide bonds.

Density Functional Theory Investigation of As(III) S-Adenosylmethionine Methyltransferase.

Arsenic is one of the most pervasive environmental toxins. It enters our water and food supply through many different routes, including the burning of fossil fuels, the application of arsenic-based herbicides, and natural sources. Using a density functional theory (DFT) cluster approach, the mechanism of arsenic (III) S-adenosylmethionine methyltransferases and various selenium-containing analogues was investigated.

Examination of sulfonamide-based inhibitors of MMP3 using the conditioned media of invasive glioma cells.

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM.

Generation and Reactions of a Benzodehydrotropylium Ion-Co(CO) Complex.

A series of 7-methylenedehydrobenzo[7]annulen-5-ol hexacarbonyldicobalt complexes were generated by Hosomi-Sakurai reactions of allylsilanes containing -alkynylarylaldehyde-Co(CO) complexes. One of the cyclization products was converted into its corresponding dihydrobenzo[7]annulen-7-ol hexacarbonyldicobalt complex, an immediate precursor to a benzodehydrotropylium-Co(CO). The cation was generated in situ and reacted with four nucleophiles, and its aromatic stabilization was determined by computational methods.

Computational Investigation into the Ni(SeNHC(CN)) and Ni(SNHC(CN)) Complexes as Potential Catalysts for Hydrogen Production.

To reduce our carbon footprint, we must look at alternative non-carbon-containing fuels to prevent continued global climate change. One environmentally friendly alternative fuel is molecular hydrogen. Herein the Ni(SeNHC(CN)) complex was studied using DFT to determine the thermodynamics associated with the electrocatalytic formation of H(g).

The Importance of the MM Environment and the Selection of the QM Method in QM/MM Calculations: Applications to Enzymatic Reactions.

In this chapter, we discuss the influence of an anisotropic protein environment on the reaction mechanisms of saccharopine reductase and uroporphyrinogen decarboxylase, respectively, via the use of a quantum mechanical and molecular mechanical (QM/MM) approach. In addition, we discuss the importance of selecting a suitable DFT functional to be used in a QM/MM study of a key intermediate in the mechanism of 8R-lipoxygenase, a nonheme iron enzyme. In the case of saccharopine reductase, while the enzyme utilizes a substrate-assisted catalytic pathway, it was found that only through treating the polarizing effect of the active site, via the use of an electronic embedding formalism, was agreement with experimental kinetic data obtained.

Assessment of several DFT functionals in calculation of the reduction potentials for Ni-, Pd-, and Pt-bis-ethylene-1,2-dithiolene and -diselenolene complexes.

We performed an assessment of 10 common DFT functionals to determine their suitability for calculating the reduction potentials of the ([M(S2C2H2)2](0)/[M(S2C2H2)2](1-)), ([M(Se2C2H2)2](0)/[M(Se2C2H2)2](1-)), ([M(S2C2H2)2](1-)/[M(S2C2H2)2](2-)), and ([M(Se2C2H2)2](1-)/[M(Se2C2H2)2](2-)) redox couples (M = Ni, Pd, and Pt). Overall it was found that the M06 functional leads to the best agreement with the gold standard CCSD(T) method with an average difference of only +0.07 V and a RMS of 0.

The catalytic formation of leukotriene C4: a critical step in inflammatory processes.

Leukotrienes (LT) are a family of drug-like molecules involved in the pathobiology of bronchial asthma and are responsible for smooth muscle contraction. Leukotriene C4 synthase (LTC4S) is a nuclear-membrane enzyme responsible for the conjugation of leukotriene A4 (LTA4) to glutathione to form LTC4, a cysteinyl leukotriene. In this study, the mechanism of LTA4 binding by LTC4S has been computationally examined.

The one-electron oxidation of a dithiolate molecule: the importance of chemical intuition.

A series of nine commonly used density functional methods were assessed to accurately predict the oxidation potential of the (C2H2S2(-2)/C2H2S2(•-)) redox couple. It was found that due to their greater tendency for charge delocalization the GGA functionals predict a structure where the radical electron is delocalized within the alkene backbone of C2H2S2(•-), whereas the hybrid functionals and the reference QCISD/cc-pVTZ predict that the radical electron remains localized on the sulfurs. However, chemical intuition suggests that the results obtained with the GGA functionals should be correct.

The one-electron reduction of dithiolate and diselenolate ligands.

Herein we present an assessment to determine which of nine well-established DFT functionals best describes the reduction of C2H2Se2(-)˙. In addition, we have also studied the effects of changing the substituents bound to the alkene functional group of dithiolene and diselenolene ligands. Such ligands are important due to their unique electrochemical and physical properties when ligated to metals.

A molecular dynamics examination on mutation-induced catalase activity in coral allene oxide synthase.

Coral allene oxide synthase (cAOS) catalyzes the formation of allene oxides from fatty acid hydroperoxides. Interestingly, its active site differs from that of catalase by only a single residue yet is incapable of catalase activity. That is, it is unable to catalyze the decomposition of hydrogen peroxide to molecular oxygen and water.

Insights into the catalytic mechanism of coral allene oxide synthase: a dispersion corrected density functional theory study.

In this present work the mechanism by which cAOS catalyzes the formation of allene oxide from its hydroperoxy substrate was computationally investigated by using a DFT-chemical cluster approach. In particular, the effects of dispersion interactions and DFT functional choice (M06, B3LYP, B3LYP*, and BP86), as well as the roles of multistate reactivity and the tyrosyl proximal ligand, were examined. It is observed that the computed relative free energies of stationary points along the overall pathway are sensitive to the choice of DFT functional, while the mechanism obtained is generally not.

A density functional theory investigation into the binding of the antioxidants ergothioneine and ovothiol to copper.

The ability of hybrid, nonhybrid and meta-GGA density functional theory (DFT) based methods (B3LYP, BP86, M06 and M06L) to provide reliable structures and thermochemical properties of biochemically important Cu(I)/(II)···ESH (ergothioneine) and ···OSH (ovothiol) has been assessed. For all functionals considered, convergence in the optimized structures and Cu(I)/(II)···S/N bond lengths is only obtained using the 6-311+G(2df,p) basis set or larger, with the nonhybrid DFT method BP86 appearing, in general, to provide the most reliable structures. The reduction potentials associated with the reduction of Cu(II) to Cu(I) when complexed with either OSH and ESH were also determined.

Gaining insight into the chemistry of lipoxygenases: a computational investigation into the catalytic mechanism of (8R)-lipoxygenase.

Lipoxygenases (LOXs) are ubiquitous in nature and catalyze a range of life-essential reactions within organisms. In particular they are critical to the formation of eicosanoids, which are critical for normal cell function. However, a number of important questions about the reactivity and mechanism of these enzymes still remain.

Model iron-oxo species and the oxidation of imidazole: insights into the mechanism of OvoA and EgtB?

A density functional theory cluster and first-principles quantum and statistical mechanics approach have been used to investigate the ability of iron-oxygen intermediates to oxidize a histidine cosubstrate, which may then allow for the possible formation of 2- and 5-histidylcysteine sulfoxide, respectively. Namely, the ability of ferric superoxo (Fe(III)O(2)(•-)), Fe(IV)═O, and ferrous peroxysulfur (Fe(III)OOS) complexes to oxidize the imidazole of histidine via an electron transfer (ET) or a proton-coupled electron transfer (PCET) was considered. While the high-valent mononuclear Fe(IV)═O species is generally considered the ultimate biooxidant, the free energies for its reduction (via ET or PCET) suggest that it is unable to directly oxidize histidine's imidazole.

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) study on Ornithine Cyclodeaminase (OCD): a tale of two iminiums.

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined.

An assessment of pure, hybrid, meta, and hybrid-meta GGA density functional theory methods for open-shell systems: the case of the nonheme iron enzyme 8R-LOX.

The performance of a range density functional theory functionals combined in a quantum mechanical (QM)/molecular mechanical (MM) approach was investigated in their ability to reliably provide geometries, electronic distributions, and relative energies of a multicentered open-shell mechanistic intermediate in the mechanism 8R-Lipoxygenase. With the use of large QM/MM active site chemical models, the smallest average differences in geometries between the catalytically relevant quartet and sextet complexes were obtained with the B3LYP(*) functional. Moreover, in the case of the relative energies between (4) II and (6) II, the use of the B3LYP(*) functional provided a difference of 0.

Molecular dynamics investigation into substrate binding and identity of the catalytic base in the mechanism of Threonyl-tRNA synthetase.

The structure and nature of the fully bound active site of Threonyl-tRNA Synthetase (ThrRS) for the second half-reaction has been investigated using molecular dynamics simulations. More specifically, we examined the ThrRS active site with both the substrate Threonyl-AMP and the cosubstrate cognate Threonyl-tRNA bound. Furthermore, we also considered the cases in which an active-site histidyl residue (His309) is either neutral or protonated.

A QM/MM-based computational investigation on the catalytic mechanism of saccharopine reductase.

Saccharopine reductase from Magnaporthe grisea, an NADPH-containing enzyme in the α-aminoadipate pathway, catalyses the formation of saccharopine, a precursor to L-lysine, from the substrates glutamate and α-aminoadipate-δ-semialdehyde. Its catalytic mechanism has been investigated using quantum mechanics/molecular mechanics (QM/MM) ONIOM-based approaches. In particular, the overall catalytic pathway has been elucidated and the effects of electron correlation and the anisotropic polar protein environment have been examined via the use of the ONIOM(HF/6-31G(d):AMBER94) and ONIOM(MP2/6-31G(d)//HF/6-31G(d):AMBER94) methods within the mechanical embedding formulism and ONIOM(MP2/6-31G(d)//HF/6-31G(d):AMBER94) and ONIOM(MP2/6-311G(d,p)//HF/6-31G(d):AMBER94) within the electronic embedding formulism.

The α-amino group of the threonine substrate as the general base during tRNA aminoacylation: a new version of substrate-assisted catalysis predicted by hybrid DFT.

Density functional theory-based methods in combination with large chemical models have been used to investigate the mechanism of the second half-reaction catalyzed by Thr-tRNA synthetase: aminoacyl transfer from Thr-AMP onto the (A76)3'OH of the cognate tRNA. In particular, we have examined pathways in which an active site His309 residue is either protonated or neutral (i.e.

Computational insights into the mechanism of porphobilinogen synthase.

Porphobilinogen synthase (PBGS) is a key enzyme in heme biosynthesis that catalyzes the formation of porphobilinogen (PBG) from two 5-aminolevulinic acid (5-ALA) molecules via formation of intersubstrate C-N and C-C bonds. The active site consists of several invariant residues, including two lysyl residues (Lys210 and Lys263; yeast numbering) that bind the two substrate moieties as Schiff bases. Based on experimental studies, various reaction mechanisms have been proposed for this enzyme that generally can be classified according to whether the intersubstrate C-C or C-N bond is formed first.

The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase.

In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated.