Pathways for Electron Transfer at MgO-Water Interfaces from Ab Initio Molecular Dynamics.

The nature of electron transfer across metal oxide-water interfaces depends significantly on the band gap of the oxide and its band edge energies relative to the potentials of relevant aqueous redox couples. Here we focus on the water interface with MgO, a prototypical wide band gap oxide whose conduction band edge is close in energy to that of water. We investigate the behavior of an excess electron at and out of equilibrium near the interface using ab initio molecular dynamics based on hybrid density functional theory. Our simulations show that under equilibrium conditions the excess electron (donated by an Al impurity in MgO) localizes to a midgap defect state comparable in energy and shape to a hydrated electron in bulk water. To characterize the electron transfer from the conduction band of MgO to interfacial product states, we dope near-equilibrium configurations of the pristine MgO-water system with Al and run short trajectories of these instantaneously out-of-equilibrium systems. We observe two distinct products associated with the excess electron: a surface-localized electron (esurf-) and an aqueous hydrogen radical (H•). The H• pathway exhibits a much higher activation barrier despite being more exoergic, making esurf- the kinetic product. Our characterization of the pathways on the basis of Marcus theory is consistent with the poor observed utility of MgO for water radiolysis. Moreover, we anticipate that the computational framework employed here will be broadly applicable to assessing electron transfer mechanisms at aqueous, photocatalytic interfaces.

Characterization of NiFe oxyhydroxide electrocatalysts by integrated electronic structure calculations and spectroelectrochemistry.

NiFe oxyhydroxide materials are highly active electrocatalysts for the oxygen evolution reaction (OER), an important process for carbon-neutral energy storage. Recent spectroscopic and computational studies increasingly support iron as the site of catalytic activity but differ with respect to the relevant iron redox state. A combination of hybrid periodic density functional theory calculations and spectroelectrochemical experiments elucidate the electronic structure and redox thermodynamics of Ni-only and mixed NiFe oxyhydroxide thin-film electrocatalysts. The UV/visible light absorbance of the Ni-only catalyst depends on the applied potential as metal ions in the film are oxidized before the onset of OER activity. In contrast, absorbance changes are negligible in a 25% Fe-doped catalyst up to the onset of OER activity. First-principles calculations of proton-coupled redox potentials and magnetizations reveal that the Ni-only system features oxidation of Ni2+ to Ni3+, followed by oxidation to a mixed Ni3+/4+ state at a potential coincident with the onset of OER activity. Calculations on the 25% Fe-doped system show the catalyst is redox inert before the onset of catalysis, which coincides with the formation of Fe4+ and mixed Ni oxidation states. The calculations indicate that introduction of Fe dopants changes the character of the conduction band minimum from Ni-oxide in the Ni-only to predominantly Fe-oxide in the NiFe electrocatalyst. These findings provide a unified experimental and theoretical description of the electrochemical and optical properties of Ni and NiFe oxyhydroxide electrocatalysts and serve as an important benchmark for computational characterization of mixed-metal oxidation states in heterogeneous catalysts.

Proton Discharge on a Gold Electrode from Triethylammonium in Acetonitrile: Theoretical Modeling of Potential-Dependent Kinetic Isotope Effects.

The discharge of protons on electrode surfaces, known as the Volmer reaction, is a ubiquitous reaction in heterogeneous electrocatalysis and plays an important role in renewable energy technologies. Recent experiments with triethylammonium (TEAH+) donating the proton to a gold electrode in acetonitrile demonstrate significantly different Tafel slopes for TEAH+ and its deuterated counterpart, TEAD+. As a result, the kinetic isotope effect (KIE) for the hydrogen evolution reaction changes considerably as a function of applied potential. Herein a vibronically nonadiabatic approach for proton-coupled electron transfer (PCET) at an electrode interface is extended to heterogeneous electrochemical processes and is applied to this system. This approach accounts for the key effects of the electrical double layer and spans the electronically adiabatic and nonadiabatic regimes, as found to be necessary for this reaction. The experimental Tafel plots for TEAH+ and TEAD+ are reproduced using physically reasonable parameters within this model. The potential-dependent KIE or, equivalently, isotope-dependent Tafel slope is found to be a consequence of contributions from excited electron-proton vibronic states that depend on both isotope and applied potential. Specifically, the contributions from excited reactant vibronic states are greater for TEAD+ than for TEAH+. Thus, the two reactions proceed by the same fundamental mechanism yet exhibit significantly different Tafel slopes. This theoretical approach may be applicable to a wide range of other heterogeneous electrochemical PCET reactions.

Theoretical analysis of the inverted region in photoinduced proton-coupled electron transfer.

Photoinduced proton-coupled electron transfer (PCET) plays a key role in a wide range of energy conversion processes, and understanding how to design systems to control the PCET rate constant is a significant challenge. Herein a theoretical formulation of PCET is utilized to identify the conditions under which photoinduced PCET may exhibit inverted region behavior. In the inverted region, the rate constant decreases as the driving force increases even though the reaction becomes more thermodynamically favorable. Photoinduced PCET will exhibit inverted region behavior when the following criteria are satisfied: (1) the overlap integrals corresponding to the ground reactant and the excited product proton vibrational wavefunctions become negligible for a low enough product vibronic state and (2) the reaction free energies associated with the lower excited product proton vibrational wavefunctions contributing significantly to the rate constant are negative with magnitudes greater than the reorganization energy. These criteria are typically not satisfied by harmonic or Morse potentials but are satisfied by more realistic asymmetric double well potentials because the proton vibrational states above the barrier correspond to more delocalized proton vibrational wavefunctions with nodal structures leading to destructive interference effects. Thus, this theoretical analysis predicts that inverted region behavior could be observed for systems with asymmetric double well potentials characteristic of hydrogen-bonded systems and that the hydrogen/deuterium kinetic isotope effect will approach unity and could even become inverse in this region due to the oscillatory nature of the highly excited vibrational wavefunctions. These insights may help guide the design of more effective energy conversion devices.

Theoretical Study of C-H Bond Cleavage via Concerted Proton-Coupled Electron Transfer in Fluorenyl-Benzoates.

Developing new strategies to activate and cleave C-H bonds is important for a broad range of applications. Recently a new approach for C-H bond activation using multi-site concerted proton-coupled electron transfer (PCET) involving intermolecular electron transfer to an oxidant coupled to intramolecular proton transfer was reported. For a series of oxidants reacting with 2-(9 H-fluoren-9-yl)benzoate, experimental studies revealed an atypical Brønsted α, defined as the slope of the logarithm of the PCET rate constant versus the logarithm of the equilibrium constant or the scaled driving force. Herein this reaction is modeled with a vibronically nonadiabatic PCET theory. Hydrogen tunneling, thermal sampling of the proton donor-acceptor mode, solute and solvent reorganization, and contributions from excited vibronic states are found to play important roles. The calculations qualitatively reproduce the experimental observation of a Brønsted α significantly less than 0.5 and explain this shallow slope in terms of exoergic processes between pairs of electron-proton vibronic states. These fundamental mechanistic insights may guide the design of more effective strategies for C-H bond activation and cleavage.

Kinetic and Mechanistic Characterization of Low-Overpotential, H2O2-Selective Reduction of O2 Catalyzed by N2O2-Ligated Cobalt Complexes.

A soluble, bis-ketiminate-ligated Co complex [Co(N2O2)] was recently shown to catalyze selective reduction of O2 to H2O2 with an overpotential as low as 90 mV. Here we report experimental and computational mechanistic studies of the Co(N2O2)-catalyzed O2 reduction reaction (ORR) with decamethylferrocene (Fc*) as the reductant in the presence of AcOH in MeOH. Analysis of the Co/O2 binding stoichiometry and kinetic studies support an O2 reduction pathway involving a mononuclear cobalt species. The catalytic rate exhibits a first-order kinetic dependence on [Co(N2O2)] and [AcOH], but no dependence on [Fc*] or [O2]. Differential pulse voltammetry and computational studies support CoIII-hydroperoxide as the catalyst resting state and protonation of this species as the rate-limiting step of the catalytic reaction. These results contrast previous mechanisms proposed for other Co-catalyzed ORR systems, which commonly feature rate-limiting protonation of a CoIII-superoxide adduct earlier in the catalytic cycle. Computational studies show that protonation is strongly favored at the proximal oxygen of the CoIII(OOH) species, accounting for the high selectivity for formation of hydrogen peroxide. Further analysis shows that a weak dependence of the ORR rate on the p Ka values of the protonated CoIII(OOH) species across a series of Co(N2O2) catalysts provides a rationale for the unusually low overpotential observed for O2 reduction to H2O2.

Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma.

BACKGROUND: Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis. METHODS: We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. RESULTS: Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-ß1 in both Rb models. CONCLUSIONS: Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.

Effects of applied voltage on water at a gold electrode interface from ab initio molecular dynamics.

Electrode-water interfaces under voltage bias demonstrate anomalous electrostatic and structural properties that are influential in their catalytic and technological applications. Mean-field and empirical models of the electrical double layer (EDL) that forms in response to an applied potential do not capture the heterogeneity that polarizable, liquid-phase water molecules engender. To illustrate the inhomogeneous nature of the electrochemical interface, Born-Oppenheimer ab initio molecular dynamics calculations of electrified Au(111) slabs interfaced with liquid water were performed using a combined explicit-implicit solvent approach. The excess charges localized on the model electrode were held constant and the electrode potentials were computed at frequent simulation times. The electrode potential in each trajectory fluctuated with changes in the atomic structure, and the trajectory-averaged potentials converged and yielded a physically reasonable differential capacitance for the system. The effects of the average applied voltages, both positive and negative, on the structural, hydrogen bonding, dynamical, and vibrational properties of water were characterized and compared to literature where applicable. Controlled-potential simulations of the interfacial solvent dynamics provide a framework for further investigation of more complex or reactive species in the EDL and broadly for understanding electrochemical interfaces in situ.

Inhomogeneity of Interfacial Electric Fields at Vibrational Probes on Electrode Surfaces.

Electric fields control chemical reactivity in a wide range of systems, including enzymes and electrochemical interfaces. Characterizing the electric fields at electrode-solution interfaces is critical for understanding heterogeneous catalysis and associated energy conversion processes. To address this challenge, recent experiments have probed the response of the nitrile stretching frequency of 4-mercaptobenzonitrile (4-MBN) attached to a gold electrode to changes in the solvent and applied electrode potential. Herein, this system is modeled with periodic density functional theory using a multilayer dielectric continuum treatment of the solvent and at constant applied potentials. The impact of the solvent dielectric constant and the applied electrode potential on the nitrile stretching frequency computed with a grid-based method is in qualitative agreement with the experimental data. In addition, the interfacial electrostatic potentials and electric fields as a function of applied potential were calculated directly with density functional theory. Substantial spatial inhomogeneity of the interfacial electric fields was observed, including oscillations in the region of the molecular probe attached to the electrode. These simulations highlight the microscopic inhomogeneity of the electric fields and the role of molecular polarizability at electrode-solution interfaces, thereby demonstrating the limitations of mean-field models and providing insights relevant to the interpretation of vibrational Stark effect experiments.

Brønsted Acid Scaling Relationships Enable Control Over Product Selectivity from O2 Reduction with a Mononuclear Cobalt Porphyrin Catalyst.

The selective reduction of O2, typically with the goal of forming H2O, represents a long-standing challenge in the field of catalysis. Macrocyclic transition-metal complexes, and cobalt porphyrins in particular, have been the focus of extensive study as catalysts for this reaction. Here, we show that the mononuclear Co-tetraarylporphyrin complex, Co(porOMe) (porOMe = meso-tetra(4-methoxyphenyl)porphyrin), catalyzes either 2e-/2H+ or 4e-/4H+ reduction of O2 with high selectivity simply by changing the identity of the Brønsted acid in dimethylformamide (DMF). The thermodynamic potentials for O2 reduction to H2O2 or H2O in DMF are determined and exhibit a Nernstian dependence on the acid pK a, while the CoIII/II redox potential is independent of the acid pK a. The reaction product, H2O or H2O2, is defined by the relationship between the thermodynamic potential for O2 reduction to H2O2 and the CoIII/II redox potential: selective H2O2 formation is observed when the CoIII/II potential is below the O2/H2O2 potential, while H2O formation is observed when the CoIII/II potential is above the O2/H2O2 potential. Mechanistic studies reveal that the reactions generating H2O2 and H2O exhibit different rate laws and catalyst resting states, and these differences are manifested as different slopes in linear free energy correlations between the log(rate) versus pK a and log(rate) versus effective overpotential for the reactions. This work shows how scaling relationships may be used to control product selectivity, and it provides a mechanistic basis for the pursuit of molecular catalysts that achieve low overpotential reduction of O2 to H2O.

Concerted proton-electron transfer reactions in the Marcus inverted region.

Electron transfer reactions slow down when they become very thermodynamically favorable, a counterintuitive interplay of kinetics and thermodynamics termed the inverted region in Marcus theory. Here we report inverted region behavior for proton-coupled electron transfer (PCET). Photochemical studies of anthracene-phenol-pyridine triads give rate constants for PCET charge recombination that are slower for the more thermodynamically favorable reactions. Photoexcitation forms an anthracene excited state that undergoes PCET to create a charge-separated state. The rate constants for return charge recombination show an inverted dependence on the driving force upon changing pyridine substituents and the solvent. Calculations using vibronically nonadiabatic PCET theory yield rate constants for simultaneous tunneling of the electron and proton that account for the results.

Targeting the Platelet-Derived Growth Factor-beta Stimulatory Circuitry to Control Retinoblastoma Seeds.

Purpose: Vitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)- PDGF-receptor ß (PDGFRß) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential. Methods: We performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRß signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds. Results: Our results demonstrated that PDGFRß signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-κB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology. Conclusions: Targeting the PDGFRß pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb.

Isolation of Primary Murine Retinal Ganglion Cells (RGCs) by Flow Cytometry.

Neurodegenerative diseases often have a devastating impact on those affected. Retinal ganglion cell (RGC) loss is implicated in an array of diseases, including diabetic retinopathy and glaucoma, in addition to normal aging. Despite their importance, RGCs have been extremely difficult to study until now due in part to the fact that they comprise only a small percentage of the wide variety of cells in the retina. In addition, current isolation methods use intracellular markers to identify RGCs, which produce non-viable cells. These techniques also involve lengthy isolation protocols, so there is a lack of practical, standardized, and dependable methods to obtain and isolate RGCs. This work describes an efficient, comprehensive, and reliable method to isolate primary RGCs from mice retinae using a protocol based on both positive and negative selection criteria. The presented methods allow for the future study of RGCs, with the goal of better understanding the major decline in visual acuity that results from the loss of functional RGCs in neurodegenerative diseases.