A Theoretical Study of Phosphoryl Transfers of Tyrosyl-DNA Phosphodiesterase I (Tdp1) and the Possibility of a “Dead-End” Phosphohistidine Intermediate

Tyrosyl-DNA phosphodiesterase I (Tdp1) is a DNA repair enzyme conserved across eukaryotes that catalyzes the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3′-phosphate of DNA. Atomic level details of the mechanism of Tdp1 are proposed and analyzed using a fully quantum mechanical, geometrically constrained model. The structural basis for the computational model is the vanadate-inhibited crystal structure of human Tdp1 (hTdp1, Protein Data Bank entry 1RFF). Density functional theory computations are used to acquire thermodynamic and kinetic data along the catalytic pathway, including the phosphoryl transfer and subsequent hydrolysis. Located transition states and intermediates along the reaction coordinate suggest an associative phosphoryl transfer mechanism with five-coordinate phosphorane intermediates. Similar to both theoretical and experimental results for phospholipase D, the proposed mechanism for hTdp1 also includes the thermodynamically favorable possibility of a four-coordinate phosphohistidine “dead-end” product

A Theoretical Study of Phosphoryl Transfers of Tyrosyl-DNA Phosphodiesterase I (Tdp1) and the Possibility of a “Dead-End” Phosphohistidine Intermediate

Tyrosyl-DNA phosphodiesterase I (Tdp1) is a DNA repair enzyme conserved across eukaryotes that catalyzes the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3′-phosphate of DNA. Atomic level details of the mechanism of Tdp1 are proposed and analyzed using a fully quantum mechanical, geometrically constrained model. The structural basis for the computational model is the vanadate-inhibited crystal structure of human Tdp1 (hTdp1, Protein Data Bank entry 1RFF). Density functional theory computations are used to acquire thermodynamic and kinetic data along the catalytic pathway, including the phosphoryl transfer and subsequent hydrolysis. Located transition states and intermediates along the reaction coordinate suggest an associative phosphoryl transfer mechanism with five-coordinate phosphorane intermediates. Similar to both theoretical and experimental results for phospholipase D, the proposed mechanism for hTdp1 also includes the thermodynamically favorable possibility of a four-coordinate phosphohistidine “dead-end” product

Computational Investigation of the Mechanism for the Activation of CO by Oxorhenium Complexes

In this paper a computational analysis (B3PW91) of the previously reported reaction of (O)­Re­(Me)­(DAAm) (<b>1</b>; DAAm = <i>N</i>,<i>N</i>-bis­(2-arylaminoethyl)­methylamine, aryl = C₆F₅) with CO to produce (CO)­Re­(OAc)­(DAAm) (<b>2</b>) is described. The data suggest that this transformation proceeds by two novel elementary steps that are of fundamental interest to the broader organometallic/inorganic community: (a) direct insertion of CO into the rhenium–methyl bond in <b>1</b> to yield the acyl intermediate (O)­Re­(Ac)­(DAAm) (<b>3</b>) and (b) 1,2-migration, in the presence of CO, of the acyl fragment in <b>3</b> to the oxo ligand to yield <b>2</b>. Evidence is provided for the first example of an insertion reaction where CO inserts directly into a M–R bond without prior formation of a CO adduct. In addition, it was shown that the addition of CO is necessary for the 1,2-migration of the acyl ligand. The data suggest that the addition of CO effectively weakens the Re–C_acyl bond in <b>3</b> and enables the facile migration of the acyl ligand

Electronic Effects on a Mononuclear Co Complex with a Pentadentate Ligand for Catalytic H₂ Evolution

Previous studies of Co catalysts for H₂ evolution have shown opposite effects between the redox potentials of Co centers and their catalytic properties such as the overpotential and turnover frequency: Co catalysts with more positive reduction potentials from structural modification display insignificant changes in the overpotential for H₂ evolution and require stronger acid for catalysis, and Co catalysts with lower overpotentials show decreased turnover frequency for H₂ evolution. In order to explore the electronic effects of a ligand scaffold on the catalytic properties for H₂ evolution by a Co complex with a pentadentate ligand, <i>N</i>,<i>N</i>-bis­(2-pyridinylmethyl)-2,2′-bipyridine-6-methanamine (DPA-Bpy), we replaced the pyridyls in DPA-Bpy with more basic isoquinoline groups. In contrast to data from previously reported studies, in the current study, a Co complex with a more positive reduction potential, resulting from the replacement of pyridyls with isoquinoline groups, leads to a lower overpotential and higher turnover frequency for both electro- and photocatalytic H₂ production in neutral aqueous solution

Time-Resolved Infrared Studies of a Trimethylphosphine Model Derivative of [FeFe]-Hydrogenase

Model compounds that structurally mimic the hydrogen-producing active site of [FeFe]-hydrogenases have been studied to explore potential ground-state electronic structure effects on reaction mechanisms compared to hexacarbonyl derivatives. The time-dependent behavior of Fe₂(μ-S₂C₃H₆)­(CO)₄(PMe)₂ (<b>A</b>) in room temperature <i>n</i>-heptane and acetonitrile solutions was examined using various ultrafast UV and visible excitation pulses with broadband IR-probe spectroscopy of the carbonyl (CO) stretching region. Ground- and excited-state electronic and CO-stretching mode vibrational properties of the possible isomers of <b>A</b> were also examined using density functional theory (DFT) computations. In <i>n</i>-heptane, 355 and 532 nm excitation resulted in short-lived (135 ± 74 ps) bands assigned to excited-state, CO-loss photoproducts. These bands decay away, forming new long-lived absorptions that are likely a mixture of isomers of both three-CO and four-CO ground-state isomers. These new bands grow in with a time scale of 214 ± 119 ps and persist for more than 100 ns. In acetonitrile, similar results are seen with a 532 nm pump, but the 355 nm data lack evidence of the longer-lived bands. In either solvent, the 266 nm pump data seem to also lack longer-lived bands, but the intensities are significantly lower in this data, making firm conclusions more difficult. We suggest that these wavelength-dependent excitation dynamics significantly alter potential mechanisms and efficiencies for light-driven catalysis

Degenerate Pathways for Metallacycle Ring Inversions: A Common Phenomenon Consistent with the Principle of Microscopic Reversibility

Competing degenerate pathways for ring inversion in organometallic complexes are proposed to be ubiquitous examples that adhere to the principle of microscopic reversibility. The NMR spectra for ring inversion of two chromium arene dicarbonyl pyridyl chelates ([Cr­{η⁶-C₆H₅(CH₂)_<i>n</i>(2-Py-κ<i>N)</i>}­(CO)₂]; 2-Py = 2-pyridyl, <i>n</i> = 2 (<b>1</b>), and 3 (<b>2</b>)) and a manganese cyclopentadienyl dicarbonyl methyl sulfide chelate ([Mn­{η⁵-C₅H₄COC­(SCH₃)₂(SCH₃-κ<i>S</i>)}­(CO)₂] (<b>3</b>)) were characterized via variable-temperature NMR spectroscopy and DFT theoretical calculations

Degenerate Pathways for Metallacycle Ring Inversions: A Common Phenomenon Consistent with the Principle of Microscopic Reversibility

Competing degenerate pathways for ring inversion in organometallic complexes are proposed to be ubiquitous examples that adhere to the principle of microscopic reversibility. The NMR spectra for ring inversion of two chromium arene dicarbonyl pyridyl chelates ([Cr­{η⁶-C₆H₅(CH₂)_<i>n</i>(2-Py-κ<i>N)</i>}­(CO)₂]; 2-Py = 2-pyridyl, <i>n</i> = 2 (<b>1</b>), and 3 (<b>2</b>)) and a manganese cyclopentadienyl dicarbonyl methyl sulfide chelate ([Mn­{η⁵-C₅H₄COC­(SCH₃)₂(SCH₃-κ<i>S</i>)}­(CO)₂] (<b>3</b>)) were characterized via variable-temperature NMR spectroscopy and DFT theoretical calculations

Metal–Ligand Synergistic Effects in the Complex Ni(η²‑TEMPO)₂: Synthesis, Structures, and Reactivity

In the current investigation, reactions of the “bow-tie” Ni­(η²-TEMPO)₂ complex with an assortment of donor ligands have been characterized experimentally and computationally. While the Ni­(η²-TEMPO)₂ complex has <i>trans</i>-disposed TEMPO ligands, proton transfer from the C–H bond of alkyne substrates (phenylacetylene, acetylene, trimethylsilyl acetylene, and 1,4-diethynylbenzene) produce <i>cis</i>-disposed ligands of the form Ni­(η²-TEMPO)­(κ¹-TEMPOH)­(κ¹-R). In the case of 1,4-diethynylbenzene, a two-stage reaction occurs. The initial product Ni­(η²-TEMPO)­(κ¹-TEMPOH)­[κ¹-<i>C</i>C­(C₆H₄)­CCH] is formed first but can react further with another equivalent of Ni­(η²-TEMPO)₂ to form the bridged complex Ni­(η²-TEMPO)­(κ¹-TEMPOH)­[κ¹-κ¹-<i>C</i>C­(C₆H₄)­C<i>C</i>]­Ni­(η²-TEMPO)­(κ¹-TEMPOH). The corresponding reaction with acetylene, which could conceivably also yield a bridging complex, does not occur. Via density functional theory (DFT), addition mechanisms are proposed in order to rationalize thermodynamic and kinetic selectivity. Computations have also been used to probe the relative thermodynamic stabilities of the <i>cis</i> and <i>trans</i> addition products and are in accord with experimental results. Based upon the computational results and the geometry of the experimentally observed product, a <i>trans</i>–<i>cis</i> isomerization must occur

Metal–Ligand Synergistic Effects in the Complex Ni(η²‑TEMPO)₂: Synthesis, Structures, and Reactivity

In the current investigation, reactions of the “bow-tie” Ni­(η²-TEMPO)₂ complex with an assortment of donor ligands have been characterized experimentally and computationally. While the Ni­(η²-TEMPO)₂ complex has <i>trans</i>-disposed TEMPO ligands, proton transfer from the C–H bond of alkyne substrates (phenylacetylene, acetylene, trimethylsilyl acetylene, and 1,4-diethynylbenzene) produce <i>cis</i>-disposed ligands of the form Ni­(η²-TEMPO)­(κ¹-TEMPOH)­(κ¹-R). In the case of 1,4-diethynylbenzene, a two-stage reaction occurs. The initial product Ni­(η²-TEMPO)­(κ¹-TEMPOH)­[κ¹-<i>C</i>C­(C₆H₄)­CCH] is formed first but can react further with another equivalent of Ni­(η²-TEMPO)₂ to form the bridged complex Ni­(η²-TEMPO)­(κ¹-TEMPOH)­[κ¹-κ¹-<i>C</i>C­(C₆H₄)­C<i>C</i>]­Ni­(η²-TEMPO)­(κ¹-TEMPOH). The corresponding reaction with acetylene, which could conceivably also yield a bridging complex, does not occur. Via density functional theory (DFT), addition mechanisms are proposed in order to rationalize thermodynamic and kinetic selectivity. Computations have also been used to probe the relative thermodynamic stabilities of the <i>cis</i> and <i>trans</i> addition products and are in accord with experimental results. Based upon the computational results and the geometry of the experimentally observed product, a <i>trans</i>–<i>cis</i> isomerization must occur

Synthesis, Characterization, and X‑ray Molecular Structure of Tantalum CCC-N-Heterocyclic Carbene (CCC-NHC) Pincer Complexes with Imidazole- and Triazole-Based Ligands

Unprecedented Ta bis­(NHC) pincer complexes have been synthesized and characterized by extension of the early-transition-metal amido methodology. The reaction of 1,3-bis­(3-butylimidazol-1-yl)­benzene diiodide (<b>1</b>) with stoichiometric and substoichiometric amounts of (<i>tert</i>-butylimido)­tris­(dimethylamido)­tantalum­(V) yielded (1,3-bis­(3-butylimidazol-1-yl-2-idene)-2-phenylene)­(<i>tert</i>-butylimido)­diiodotantalum­(V) (<b>2</b>) and (1,3-bis­(3-butylimidazol-1-yl-2-idene)-2-phenylene)­(<i>tert</i>-butylimido)­(dimethylamido)­iodotantalum­(V) (<b>3</b>). Use of excess (<i>tert</i>-butylimido)­tris­(dimethylamido)­tantalum­(V) to metalate 1,3-bis­(3-butylimidazol-1-yl)­benzene diiodide (<b>1</b>) yielded (1,3-bis­(3-butylimidazol-1-yl-2-idene)-2-phenylene)­(<i>tert</i>-butylimido)­(dimethylamido)­iodotantalum­(V) (<b>3</b>) exclusively. Furthermore, the first early-transition-metal (group 3–5) triazole-based NHC complex, (1,3-bis­(3-butyltriazol-1-yl-2-idene)-2-phenylene)­(<i>tert</i>-butylimido)­(dimethylamido)­iodotantalum­(V) (<b>5</b>), has been synthesized via amine elimination of 1,3-bis­(3-butyltriazol-1-yl)­benzene diiodide (<b>4</b>) with (<i>tert</i>-butylimido)­tris­(dimethylamido)­tantalum­(V)