• Boosting Self-Trapped Emissions in Zero-Dimensional Perovskite Heterostructures

      Yin, Jun; Brédas, Jean-Luc; Bakr, Osman M.; Mohammed, Omar F.; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2020-05-22)
      Zero-dimensional (0D) inorganic perovskites have attracted great interest for white-light-emitting applications because of their broad band emissions originating from self-trapped excitons. In this work, we explore and decipher exciton self-trapping in a series of 0D inorganic perovskites, A4PbX6 and A4SnX6 (A = K, Rb, and Cs; X = Cl, Br, and I) at the density functional theory level within the theoretical framework of the one-dimensional configuration coordinate diagram. We demonstrate that the formation of self-trapped states in A4PbX6 and A4SnX6 can be attributed to local structural distortions of individual [PbX6]4– and [SnX6]4– octahedra. Importantly, with the goal of both potentially improving the stability of the Sn derivatives and enhancing the emission efficiency, we further propose and design two types of 0D perovskite heterostructures, bulk A4PbX6/A4SnX6 mixtures and A4PbX6/A4SnX6 heterojunctions. We find that these 0D heterostructures exhibit type-I energy level alignment in which energy transfer from A4PbX6 to A4SnX6 is strongly promoted. Interestingly, these heterostructures show an increase in the transition dipole moments between the ground and self-trapped states compared to the pristine 0D perovskites. Our findings provide a new material design strategy for boosting self-trapped emissions with improved air stability for white-light-emitting applications.
    • Changes to the TDP-43 and FUS Interactomes Induced by DNA Damage

      Kawaguchi, Tetsuya; Rollins, Matthew G.; Moinpour, Mahta; Morera, Andres A.; Ebmeier, Christopher C.; Old, William M.; Schwartz, Jacob C.; Univ Arizona, Dept Mol & Cellular Biol; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2019-11-06)
      The RNA-binding proteins TDP-43 and FUS are tied as the thirdleading known genetic cause for amyotrophic lateral sclerosis (ALS), and TDP-43proteopathies are found in nearly all ALS patients. Both the natural function andcontribution to pathology for TDP-43 remain unclear. The intersection offunctions between TDP-43 and FUS can focus attention for those natural functionsmostly likely to be relevant to disease. Here, we compare the role played by TDP-43 and FUS, maintaining chromatin stability for dividing HEK293T cells. We alsodetermine and compare the interactomes of TDP-43 and FUS, quantitatingchanges in those before and after DNA damage. Finally, selected interactions withknown importance to DNA damage repair were validated by co-immunoprecipi-tation assays. This study uncovered TDP-43 and FUS binding to several factorsimportant to DNA repair mechanisms that can be replication-dependent,-independent, or both. These results provide further evidence that TDP-43 has an important role in DNA stability andprovide new ways that TDP-43 can bind to the machinery that guards DNA integrity in cells.
    • DNA Binding and Cleavage by the Human Parvovirus B19 NS1 Nuclease Domain

      Sanchez, Jonathan L.; Romero, Zachary; Quinones, Angelica; Torgeson, Kristiane R.; Horton, Nancy C.; Department of Chemistry and Biochemistry, University of Arizona (AMER CHEMICAL SOC, 2016-11-29)
      Infection with human parvovirus B19 (B19V) has been associated with a myriad of illnesses, including erythema infectiosum (Fifth disease), hydrops fetalis, arthropathy, hepatitis, and cardiomyopathy, and also possibly the triggering of any number of different autoimmune diseases. B19V NS1 is a multidomain protein that plays a critical role in viral replication, with predicted nuclease, helicase, and gene transactivation activities. Herein, we investigate the biochemical activities of the nuclease domain (residues 2-176) of B19V NS1 (NS1-nuc) in sequence-specific DNA binding of the viral origin of replication sequences, as well as those of promoter sequences, including the viral p6 and the human p21, TNF alpha, and IL-6 promoters previously identified in NS1-dependent transcriptional transactivation. NS1-nuc was found to bind with high cooperativity and with multiple (five to seven) copies to the NS1 binding elements (NSBE) found in the viral origin of replication and the overlapping viral p6 promoter DNA sequence. NS1-nuc was also found to bind cooperatively with at least three copies to the GC-rich Spl binding sites of the human p21 gene promoter. Only weak or nonspecific binding of NS1-nuc to the segments of the TNF alpha and IL-6 promoters was found. Cleavage of DNA by NS1-nuc occurred at the expected viral sequence (the terminal resolution site), but only in single-stranded DNA, and NS1-nuc was found to covalently attach to the 5' end of the DNA at the cleavage site. Off-target cleavage by NS1-nuc was also identified.
    • High-Throughput Experimental Study of Wurtzite Mn1–xZnxO Alloys for Water Splitting Applications

      Ndione, Paul F.; Ratcliff, Erin L.; Dey, Suhash R.; Warren, Emily L.; Peng, Haowei; Holder, Aaron M.; Lany, Stephan; Gorman, Brian P.; Al-Jassim, Mowafak M.; Deutsch, Todd G.; et al. (AMER CHEMICAL SOC, 2019-04-24)
      We used high-throughput experimental screening methods to unveil the physical and chemical properties of Mn1-xZnxO wurtzite alloys and identify their appropriate composition for effective water splitting application. The Mn1-xZnxO thin films were synthesized using combinatorial pulsed laser deposition, permitting for characterization of a wide range of compositions with x varying from 0 to 1. The solubility limit of Mn1-xZnxO was determined using the disappearing phase method from X-ray diffraction and X-ray fluorescence data and found to increase with decreasing substrate temperature due to kinetic limitations of the thin-film growth at relatively low temperature. Optical measurements indicate the strong reduction of the optical band gap down to 2.1 eV at x = 0.5 associated with the rock salt-to-wurtzite structural transition in Mn1-xZnxO alloys. Transmission electron microscopy results show evidence of a homogeneous wurtzite alloy system for a broad range of Mn1-xZnxO compositions above x = 0.4. The wurtzite Mn1-xZnxO samples with the 0.4 < x < 0.6 range were studied as anodes for photoelectrochemical water splitting, with a maximum current density of 340 mu A cm(-2) for 673 nm-thick films. These Mn1-xZnxO films were stable in pH = 10, showing no evidence of photocorrosion or degradation after 24 h under water oxidation conditions. Doping Mn1-xZnxO materials with Ga dramatically increases the electrical conductivity of Mn1-xZnxO up to similar to 1.9 S/cm for x = 0.48, but these doped samples are not active in water splitting. Mott-Schottky and UPS/ XPS measurements show that the presence of dopant atoms reduces the space charge region and increases the number of midgap surface states. Overall, this study demonstrates that Mn1-xZnxO alloys hold promise for photoelectrochemical water splitting, which could be enhanced with further tailoring of their electronic properties.
    • Influence of Molecular Aggregation on Electron Transfer at the Perylene Diimide/Indium-Tin Oxide Interface

      Zheng, Yilong; Jradi, Fadi M.; Parker, Timothy C.; Barlow, Stephen; Marder, Seth R.; Saavedra, S. Scott; Department of Chemistry & Biochemistry, University of Arizona (AMER CHEMICAL SOC, 2016-12-14)
      Chemisorption of an organic monolayer to tune the surface properties of a transparent conductive oxide (TCO) electrode can improve the performance of organic electronic devices that rely on efficient charge transfer between an organic active layer and a TCO contact. Here, a series of perylene diimides (PDIs) was synthesized and used to study relationships between monolayer structure/properties and electron transfer kinetics at PDI-modified indium-tin oxide (ITO) electrodes. In these PDI molecules, one of the imide substituents is a benzene ring bearing a phosphonic acid (PA) and the other is a bulky aryl group that is twisted out of the plane of the PDI core. The size of the bulky aryl group and the substitution of the benzene ring bearing the PA were both varied, which altered the extent of aggregation when these molecules were absorbed as monolayer films (MLs) on ITO, as revealed by both attenuated total reflectance (ATR) and total internal reflection fluorescence spectra. Polarized ATR measurements indicate that, in these MLs, the long axis of the PDI core is tilted at an angle of 33-42 degrees relative to the surface normal; the tilt angle increased as the degree of bulky substitution increased. Rate constants for electron transfer (k(s,opt)) between these redox-active modifiers and ITO were determined by potential-modulated ATR spectroscopy. As the degree of PDI aggregation was reduced, k(s,opt) declined, which is attributed to a reduction in the lateral electron self-exchange rate between adsorbed PDI molecules, as well as the heterogeneous conductivity of the ITO electrode surface. Photoelectrochemical measurements using a dissolved aluminum phthalocyanine as an electron donor showed that ITO modified with any of these PDIs is a more effective electron-collecting electrode than bare ITO.
    • A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III 1

      Sutherland, Caleb; Cui, Yunxi; Mao, Hanbin; Hurley, Laurence H.; University of Arizona Cancer Center; University of Arizona, College of Pharmacy (AMER CHEMICAL SOC, 2016-10-26)
      MYC is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of MYC is complex, and the NHE III1 and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1 only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation. For maximal hnRNP K transcription activation, two additional cytosine runs, located seven bases downstream of the i-motif-forming region, are also required. To access these additional runs of cytosine, increased negative superhelicity is necessary, which leads to a thermodynamically stable complex between hnRNP K and the unfolded i-motif. We also demonstrate mutual exclusivity between the MYC G-quadruplex and i-motif, providing a rationale for a molecular switch mechanism driven by SP1-induced negative superhelicity, where relative hnRNP K and nucleolin expression shifts the equilibrium to the on or off state.
    • Modulation of Broadband Emissions in Two-Dimensional ⟨100⟩-Oriented Ruddlesden–Popper Hybrid Perovskites

      Yin, Jun; Naphade, Rounak; Gutiérrez Arzaluz, Luis; Brédas, Jean-Luc; Bakr, Osman M.; Mohammed, Omar F.; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2020-05-28)
      Two-dimensional (2D) Ruddlesden–Popper (RP) perovskites are emerging materials for light-emitting applications. Unfortunately, their desirable narrowband emission coexists with broadband emissions, which limits the color quality and performance of the light source. However, the origin of such broadband emission in ⟨100⟩-oriented perovskites is still under debate. Here, we experimentally and theoretically demonstrate that unlike ⟨110⟩-oriented RP perovskites, the broadband emission of the 2D ⟨100⟩-oriented RP (PEA)2PbI4 (PEA = C6H5C2H4NH3+) perovskites originates from defect-related luminescence centers. We find that the broadband emission of this prototype 2D structure can be largely suppressed by using excess PEAI treatment. Density functional theory (DFT) calculations indicate that iodine (I) vacancies both in the bulk and on the surface are responsible for the broadband emission. We attribute the decreased broadband emission after PEAI treatment to the passivation of both undercoordinated Pb2+ ions on the surface and I vacancies in the bulk through I– ion migration.
    • Multiple Reaction Pathways in the Morphinone Reductase-Catalyzed Hydride Transfer Reaction

      Chen, Xi; Schwartz, Steven D.; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2020-09)
      Morphinone reductase (MR) is an important model system for studying the contribution of protein motions to H-transfer reactions. In this research, we used quantum mechanical/molecular mechanics (QM/MM) simulation together with transition path sampling (TPS) simulation to study two important topics of current research on MR: the existence of multiple catalytic reaction pathways and the involvement of fast protein motions in the catalytic process. We have discovered two reaction pathways for the wild type and three reaction pathways for the N189A mutant. With the committor distribution analysis method, we found reaction coordinates for all five reaction pathways. Only one wild-type reaction pathway has a rate-promoting vibration from His186, while all of the other four pathways do not involve any protein motions in their catalytic process through the transition state. The rate-promoting vibration in the wild-type MR, which comes from a direction perpendicular to the donor-acceptor axis, functions to decrease the donor-acceptor distance by causing a subtle "out-of-plane" motion of a donor atom. By comparing reaction pathways between the two enzymes, we concluded that the major effect of the N189A point mutation is to increase the active site volume by altering the active site backbone and eliminating the Asn189 side chain. This effect causes a different NADH geometry at the reactant state, which very well explains the different reaction mechanisms between the two enzymes, as well as the disappearance of the His186 rate-promoting vibrations in the N189A mutant. The unfavorable geometry of the NADH pyridine ring induced by the N189A point mutation is the potential cause of multiple reaction pathways in N189A mutants.
    • Nitrate Reverses Severe Nitrite Inhibition of Anaerobic Ammonium Oxidation (Anammox) Activity in Continuously-Fed Bioreactors

      Li, Guangbin; Sierra-Alvarez, Reyes; Vilcherrez, David; Weiss, Stefan; Gill, Callie; Krzmarzick, Mark J; Abrell, Leif; Field, Jim A.; University of Arizona (AMER CHEMICAL SOC, 2016-10-04)
      Nitrite (NO2-) substrate under certain conditions can cause failure of N-removal processes relying on anaerobic ammonium oxidizing (anammox) bacteria. Detoxification of NO2- can potentially be achieved by using exogenous nitrate (NO3-). In this work, continuous experiments in bioreactors with anammox bacteria closely related to “Candidatus Brocadia caroliniensis” were conducted to evaluate the effectiveness of short NO3- additions to reverse NO2- toxicity. The results show that a timely NO3- addition immediately after a NO2- stress event completely reversed the NO2- inhibition. This reversal occurs without NO3- being metabolized as evidence by lack of any 30N2 formation from 15N-NO3-. The maximum recovery rate was observed with 5 mM NO3- added for 3 days; however, slower but significant recovery was also observed with 5 mM NO3- for 1 day or 2 mM NO3- for 3 days. Without NO3- addition, long-term NO2- inhibition of anammox biomass resulted in irreversible damage of the cells. These results suggest that a short duration dose of NO3- to an anammox bioreactor can rapidly restore the activity of NO2--stressed anammox cells. On the basis of the results, a hypothesis about the detoxification mechanism related to narK genes in anammox bacteria is proposed and discussed.
    • A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

      Kang, Hyun-Jin; Cui, Yunxi; Yin, Holly; Scheid, Amy; Hendricks, William P. D.; Schmidt, Jessica; Sekulic, Aleksandar; Kong, Deming; Trent, Jeffrey M.; Gokhale, Vijay; et al. (AMER CHEMICAL SOC, 2016-10-19)
      Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding-sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress, hTERT.
    • Proof of Principle that Molecular Modeling Followed by a Biophysical Experiment Can Develop Small Molecules that Restore Function to the Cardiac Thin Filament in the Presence of Cardiomyopathic Mutations

      Szatkowski, Lukasz; Lynn, Melissa L.; Holeman, Teryn; Williams, Michael R.; Baldo, Anthony P.; Tardiff, Jil C.; Schwartz, Steven D.; Univ Arizona, Dept Med; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2019-04-09)
      This article reports a coupled computational experimental approach to design small molecules aimed at targeting genetic cardiomyopathies. We begin with a fully atomistic model of the cardiac thin filament. To this we dock molecules using accepted computational drug binding methodologies. The candidates are screened for their ability to repair alterations in biophysical properties caused by mutation. Hypertrophic and dilated cardiomyopathies caused by mutation are initially biophysical in nature, and the approach we take is to correct the biophysical insult prior to irreversible cardiac damage. Candidate molecules are then tested experimentally for both binding and biophysical properties. This is a proof of concept study-eventually candidate molecules will be tested in transgenic animal models of genetic sarcomeric cardiomyopathies.
    • Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length

      Dickerhoff, Jonathan; Onel, Buket; Chen, Luying; Chen, Yuwei; Yang, Danzhou; Univ Arizona, Coll Sci, Dept Chem & Biochem (AMER CHEMICAL SOC, 2019-02-28)
      The important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5'-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.
    • Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands

      Wu, Zhijun; Hruby, Victor J; Univ Arizona, Dept Chem & Biochem (AMER CHEMICAL SOC, 2019-10-22)
      Opioid ligands are a large group of G-protein-coupled receptor ligands possessing high structural diversity, along with complicated structure–activity relationships (SARs). To better understand their structural correlations as well as the related SARs, we developed the innovative template-based alignment modeling in our recent studies on a variety of opioid ligands. As previously reported, this approach showed promise but also with limitations, which was mainly attributed to the small size of morphine as a template. With this study, we set out to construct an artificial μ-agonist template to overcome this limitation. The newly constructed template contained a largely extended scaffold, along with a few special μ-features relevant to the μ-selectivity of opioid ligands. As demonstrated in this paper, the new template showed significantly improved efficacy in facilitating the alignment modeling of a wide variety of opioid ligands. This report comprises of two main parts. Part 1 discusses the general construction process and the structural features as well as a few typical examples of the template applications and Part 2 focuses on the template refinement and validation.
    • Tsuji-Trost Cyclization of Disulfonamides: Synthesis of 12-Membered, 11-Membered, and Pyridine-Fused Macrocyclic Triamines

      Ali, Rameez; Anugu, Sreenivasa; Chawla, Reena; Demillo, Violeta G; Goulinet-Mateo, Florian; Gyawali, Sagar; Hamal, Sunil; Jones, Dylan E; Lamprecht, Katrin; Le, Truc; et al. (AMER CHEMICAL SOC, 2019-01-31)
      Macrocyclic triamine disulfonamides can be synthesized by double Tsuji-Trost N-allylation reaction of open-chain disulfonamides with 2-alkylidene-1,3-propanediyl bis(carbonates). The previously used Atkins-Richman macrocyclization method generally gives lower yields and requires more tedious purification of the product. Solvent, palladium source, ligand, and concentration have all been varied to optimize the yields of two key 12-membered ring bioactive compounds, CADA and VGD020. The new approach tolerates a wide range of functional groups and gives highest yields for symmetrical compounds in which the acidities of the two sulfonamide groups are matched, although the yields of unsymmetrical compounds are still generally good. The method has also been extended to the synthesis of 11-membered rings, pyridine-fused macrocycles, and products bearing an ester or aryl substituent on the exocyclic double bond.