Benjamin F. Gherman

How iron-containing proteins control dioxygen chemistry: a detailed atomic level description via accurate quantum chemical and mixed quantum mechanics/molecular mechanics calculations

Abstract Over the past several years, rapid advances in computational hardware, quantum chemical methods, and mixed quantum mechanics/molecular mechanics (QM/MM) techniques have made it possible to model accurately the interaction of ligands with metal-containing proteins at an atomic level of detail. In this paper, we describe the application of our computational methodology, based on density functional (DFT) quantum chemical methods, to two diiron-containing proteins that interact with dioxygen: methane monooxygenase (MMO) and hemerythrin (Hr). Although the active sites are structurally related, the biological function differs substantially. MMO is an enzyme found in methanotrophic bacteria and hydroxylates aliphatic C–H bonds, whereas Hr is a carrier protein for dioxygen used by a number of marine invertebrates. Quantitative descriptions of the structures and energetics of key intermediates and transition states involved in the reaction with dioxygen are provided, allowing their mechanisms to be compared and contrasted in detail. An in-depth understanding of how the chemical identity of the first ligand coordination shell, structural features, electrostatic and van der Waals interactions of more distant shells control ligand binding and reactive chemistry is provided, affording a systematic analysis of how iron-containing proteins process dioxygen. Extensive contact with experiment is made in both systems, and a remarkable degree of accuracy and robustness of the calculations is obtained from both a qualitative and quantitative perspective.

Characterization of the structure and reactivity of monocopper–oxygen complexes supported by β-diketiminate and anilido-imine ligands

Copper–oxygen complexes supported by β‐diketiminate and anilido‐imine ligands have recently been reported (Aboelella et al., J Am Chem Soc 2004, 126, 16896; Reynolds et al., Inorg Chem 2005, 44, 6989) as potential biomimetic models for dopamine β‐monooxygenase (DβM) and peptidylglycine α‐hydroxylating monooxygenase (PHM). However, in contrast to the enzymatic systems, these complexes fail to exhibit CH hydroxylation activity (Reynolds et al., Chem Commun 2005, 2014). Quantum chemical characterization of the 1:1 Cu‐O2 model adducts and related species (Cu(III)‐hydroperoxide, Cu(III)‐oxo, and Cu(III)‐hydroxide) indicates that the 1:1 Cu‐O2 adducts are unreactive toward substrates because of the weakness of the OH bond that would be formed upon hydrogen‐atom abstraction. This in turn is ascribed to the 1:1 adducts having both low reduction potentials and basicities. Cu(III)‐oxo species on the other hand, determined to be intermediate between Cu(III)‐oxo and Cu(II)‐oxyl in character, are shown to be far more reactive toward substrates. Based on these results, design strategies for new DβM and PHM biomimetic ligands are proposed: new ligands should be made less electron rich so as to favor end‐on dioxygen coordination in the 1:1 Cu‐O2 adducts. Comparison of the relative reactivities of the various copper–oxygen complexes as hydroxylating agents provides support for a Cu(II)‐superoxide species as the intermediate responsible for substrate hydroxylation in DβM and PHM, and suggests that a Cu(III)‐oxo intermediate would be competent in this process as well.

Photodissociation of acetaldehyde: The CH4+CO channel

Ab initio quantum chemical calculations for the molecular dissociation channel of acetaldehyde are reported. The enthalpy change for the dissociation of acetaldehyde into methane and carbon monoxide was calculated to be exoergic by 1.7 kcal/mol. The transition state for this unimolecular dissociation, confirmed by normal mode analysis, was found to have an activation energy of 85.3 kcal/mol. Experimental measurements are reported for the vibrational and rotational state distribution of the CO product. No v=1 CO is found and the rotational temperature is 1300±90 K. The reaction coordinate at the transition state implies that the CO product is vibrationally cold and rotationally hot. This conclusion, which requires quantum dynamics calculations to confirm definitively, does agree with and aids in explaining the experimental results.

Coulomb screening and exciton binding energies in conjugated polymers

Hartree–Fock solutions of the Pariser–Parr–Pople and MNDO Hamiltonians are shown to give reasonable predictions for the ionization potentials and electron affinities of gas-phase polyenes. However, the energy predicted for formation of a free electron-hole pair on an isolated chain of polyacetylene is much larger than that seen in the solid state. The prediction is 6.2 eV if soliton formation is ignored and about 4.7 eV if soliton formation is included. The effects of interchain interactions on the exciton binding energy are then explored using a model system consisting of one solute and one solvent polyene, that are coplanar and separated by 4 A. The lowering of the exciton binding energy is calculated by comparing the solvation energy of the exciton state to that of a single hole (a cationic solute polyene) and a single electron (an anionic solute polyene). It is argued that when the relative timescales of charge fluctuations on the solute and solvent chains are taken into account, it is difficult to ra...

Models for dioxygen activation by the CuB site of dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase

On the basis of spectroscopic and crystallographic data for dopamine β-monooxygenase and peptidylglycine α-hydroxylating monooxygenase (PHM), a variety of ligand sets have been used to model the oxygen-binding Cu site in these enzymes. Calculations which employed a combination of density functional and multireference second-order perturbation theory methods provided insights into the optimal ligand set for supporting η1 superoxo coordination as seen in a crystal structure of a precatalytic Cu/O2 complex for PHM (Prigge et al. in Science 304:864–867, 2004). Anionic ligand sets stabilized η2 dioxygen coordination and were found to lead to more peroxo-like Cu–O2 complexes with relatively exergonic binding free energies, suggesting that these adducts may be unreactive towards substrates. Neutral ligand sets (including a set of two imidazoles and a thioether), on the other hand, energetically favored η1 dioxygen coordination and exhibited limited dioxygen reduction. Binding free energies for the 1:1 adducts with Cu supported by the neutral ligand sets were also higher than with their anionic counterparts. Deviations between the geometry and energetics of the most analogous models and the PHM crystal structures suggest that the protein environment influences the coordination geometry at the CuB site and increases the lability of water bound to the preoxygenated reduced form. Another implication is that a neutral ligand set will be critical in biomimetic models in order to stabilize η1 dioxygen coordination.

Quantum chemical studies of methane monooxygenase: comparision with P450.

The catalytic pathways of soluble methane monooxygenase (sMMO) and cytochrome P450CAM, iron-containing enzymes, are described and compared. Recent extensive density functional ab initio electronic structure calculations have revealed many similarities in a number of the key catalytic steps, as well as some important differences. A particularly interesting and significant contrast is the role played by the protein in each system. For sMMO, the protein stabilizes various species in the catalytic cycle through a series of carboxylate shifts. This process is adequately described by a relatively compact model of the active site ( approximately 100 atoms), providing a reasonable description of the energetics of hydrogen atom abstraction. For P450CAM, in contrast, the inclusion of the full protein is necessary for an accurate description of the hydrogen atom abstraction.

Syntheses, thermal reactivities, and computational studies of aryl-fused quinoxalenediynes: effect of extended benzannelation on Bergman cyclization energetics.

A series of [b]-fused 6,7-diethynylquinoxaline derivatives have been synthesized through an imine condensation strategy to examine the effect of extended benzannelation on the thermal reactivity of enediynes. Absorption and emission spectra of the highly conjugated quinoxalenediynes were red-shifted approximately 100-200 nm relative to those of 1,2-diethynylbenzene. Strong exotherms indicative of enediyne cyclization were observed by differential scanning calorimetry, while solution cyclizations in the presence of 1,4-cyclohexadiene confirmed C(1)-C(6) Bergman cyclization. To provide further insight into Bergman cyclization energetics, computational studies were performed to compare changes in the cyclization enthalpy barrier, reaction enthalpy, and barrier of retro-Bergman ring-opening. Extension of benzannelation from 1,2-diethynylbenzene to either 2,3-diethynylnaphthalene or the 6,7-diethynylquinoxalines had a minimal effect on the cyclization barrier. In comparison, the enthalpies of cyclization were increased upon linearly extended benzannelation, which resulted in reduced barriers to retro-Bergman ring-opening. In addition, the orientation of extended benzannelation was found to have a significant effect on the cyclization endothermicity. In particular, 5,6-diethynylquinoxaline exhibited a 6.9 kcal/mol decrease in cyclization enthalpy compared to 6,7-diethynylquinoxaline due to increased aromatic stabilization energy in the respective angularly versus linearly fused azaacene cyclized products.

Comparison of the INDO band structures of polyacetylene, polythiophene, polyfuran, and polypyrrole

The intermediate neglect of differential overlap (INDO) band structures of polythiophene, polyfuran, and polypyrrole are analyzed in terms of the band structure of polyacetylene. This is done by decoupling the INDO Fock operator to obtain the band structure of the carbon system and of the heteroatoms. For all three polymer systems, the highest valence band is essentially a pure carbon band, whereas the lowest conduction band is a strong mixture of carbon and heteroatom bands. This suggests that the electron and hole should show distinct properties. This difference between the electron and hole can be understood in terms of coupling between the respective Wannier functions of polyacetylene and the heteroatoms. Polypyrrole shows a stronger coupling between the carbon and heteroatom bands than polythiophene or polyfuran.

Syntheses and Reactivity of Naphthalenyl-Substituted Arenediynes

A series of naphthalenyl-substituted arenediynes were prepared to examine photochemical reactivity. For naphthalen-1-ylethynyl arenediyne, 350 nm photolysis resulted in a tandem [2 + 2] photocycloaddition to afford cyclobutene adducts. For naphthalen-2-ylethynyl derivatives, electron-donating methoxy substituents were found to facilitate C(1)-C(6) Bergman cyclization at 300 nm. Theoretical calculations provided further insight into thermal and photochemical reactivity.

Prediction of reduction potentials from calculated electron affinities for metal-salen compounds

Summary The electron affinities (EAs) of a training set of 19 metal-salen compounds were calculated using density functional theory. Concurrently, the experimental reduction potentials for the training set were measured using cyclic voltammetry. The EAs and reduction potentials were found to be linearly correlated by metal. The reduction potentials of a test set of 14 different metal-salens were then measured and compared to the predicted reduction potentials based upon the training set correlation. The method was found to work well, with a mean unsigned error of 99 mV for the entire test set. This method could be used to predict the reduction potentials of a variety of metal-salen compounds, an important class of coordination compounds used in synthetic organic electrochemistry as electrocatalysts.