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Sample records for backbone metal cyclization

  1. Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase

    PubMed Central

    Harris, Karen S.; Durek, Thomas; Kaas, Quentin; Poth, Aaron G.; Gilding, Edward K.; Conlan, Brendon F.; Saska, Ivana; Daly, Norelle L.; van der Weerden, Nicole L.; Craik, David J.; Anderson, Marilyn A.

    2015-01-01

    Cyclotides are diverse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express OaAEP1b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, OaAEP1b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant OaAEP1b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired. PMID:26680698

  2. Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase.

    PubMed

    Harris, Karen S; Durek, Thomas; Kaas, Quentin; Poth, Aaron G; Gilding, Edward K; Conlan, Brendon F; Saska, Ivana; Daly, Norelle L; van der Weerden, Nicole L; Craik, David J; Anderson, Marilyn A

    2015-01-01

    Cyclotides are diverse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express OaAEP1b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, OaAEP1b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant OaAEP1b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired. PMID:26680698

  3. Changing the topology of protein backbone: the effect of backbone cyclization on the structure and dynamics of a SH3 domain

    PubMed Central

    Schumann, Frank H.; Varadan, Ranjani; Tayakuniyil, Praveen P.; Grossman, Jennifer H.; Camarero, Julio A.; Fushman, David

    2015-01-01

    Understanding of the effects of the backbone cyclization on the structure and dynamics of a protein is essential for using protein topology engineering to alter protein stability and function. Here we have determined, for the first time, the structure and dynamics of the linear and various circular constructs of the N-SH3 domain from protein c-Crk. These constructs differ in the length and amino acid composition of the cyclization region. The backbone cyclization was carried out using intein-mediated intramolecular chemical ligation between the juxtaposed N- and the C-termini. The structure and backbone dynamics studies were performed using solution NMR. Our data suggest that the backbone cyclization has little effect on the overall three-dimensional structure of the SH3 domain: besides the termini, only minor structural changes were found in the proximity of the cyclization region. In contrast to the structure, backbone dynamics are significantly affected by the cyclization. On the subnanosecond time scale, the backbone of all circular constructs on average appears more rigid than that of the linear SH3 domain; this effect is observed over the entire backbone and is not limited to the cyclization site. The backbone mobility of the circular constructs becomes less restricted with increasing length of the circularization loop. In addition, significant conformational exchange motions (on the sub-millisecond time scale) were found in the N-Src loop and in the adjacent β-strands in all circular constructs studied in this work. These effects of backbone cyclization on protein dynamics have potential implications for the stability of the protein fold and for ligand binding. PMID:25905098

  4. Stabilization of α-conotoxin AuIB: influences of disulfide connectivity and backbone cyclization.

    PubMed

    Lovelace, Erica S; Gunasekera, Sunithi; Alvarmo, Charlotta; Clark, Richard J; Nevin, Simon T; Grishin, Anton A; Adams, David J; Craik, David J; Daly, Norelle L

    2011-01-01

    α-Conotoxins are peptides isolated from the venom ducts of cone snails that target nicotinic acetylcholine receptors (nAChRs). They are valuable pharmacological tools and have potential applications for treating a range of conditions in humans, including pain. However, like all peptides, conotoxins are susceptible to degradation, and to enhance their therapeutic potential it is important to elucidate the factors contributing to instability and to develop approaches for improving stability. AuIB is a unique member of the α-conotoxin family because the nonnative "ribbon" disulfide isomer exhibits enhanced activity at the nAChR in rat parasympathetic neurons compared with the native "globular" isomer. Here we show that the ribbon isomer of AuIB is also more resistant to disulfide scrambling, despite having a nonnative connectivity and flexible structure. This resistance to disulfide scrambling does not correlate with overall stability in serum because the ribbon isomer is degraded in human serum more rapidly than the globular isomer. Cyclization via the joining of the N- and C-termini with peptide linkers of four to seven amino acids prevented degradation of the ribbon isomer in serum and stabilized the globular isomers to disulfide scrambling. The linker length used for cyclization strongly affected the relative proportions of the disulfide isomers produced by oxidative folding. Overall, the results of this study provide important insights into factors influencing the stability and oxidative folding of α-conotoxin AuIB and might be valuable in the design of more stable antagonists of nAChRs.

  5. Green chemistry: solvent- and metal-free Prins cyclization. Application to sequential reactions.

    PubMed

    Clarisse, Damien; Pelotier, Béatrice; Piva, Olivier; Fache, Fabienne

    2012-01-01

    Prins cyclization between a homoallylic alcohol and an aldehyde, promoted by trimethylsilyl halide, afforded 4-halo-tetrahydropyrans with good to excellent yields. Thanks to the absence of the solvent and metal, the THP thus obtained have been implicated without purification in several other reactions, in a sequential way, affording in particular new indole derivatives. PMID:22068454

  6. Green chemistry: solvent- and metal-free Prins cyclization. Application to sequential reactions.

    PubMed

    Clarisse, Damien; Pelotier, Béatrice; Piva, Olivier; Fache, Fabienne

    2012-01-01

    Prins cyclization between a homoallylic alcohol and an aldehyde, promoted by trimethylsilyl halide, afforded 4-halo-tetrahydropyrans with good to excellent yields. Thanks to the absence of the solvent and metal, the THP thus obtained have been implicated without purification in several other reactions, in a sequential way, affording in particular new indole derivatives.

  7. Acid-Catalyzed Multicomponent Tandem Double Cyclization: A One-pot, Metal-free Route to Synthesize Polyfunctional 4,9-Dihydropyrrolo[2,1-b]quinazolines.

    PubMed

    Cai, Qun; Li, Deng-Kui; Zhou, Rong-Rong; Zhuang, Shi-Yi; Ma, Jin-Tian; Wu, Yan-Dong; Wu, An-Xin

    2016-09-01

    An acid-catalyzed multicomponent tandem double cyclization protocol has been developed for the synthesis of polyfunctional 4,9-dihydropyrrolo[2,1-b]quinazolines from simple and readily available arylglyoxal monohydrates, 2-aminobenzylamine, and trans-β-nitrostyrenes. This practical and metal-free reaction proceeds through an imine formation/cyclization/Michael addition/Henry cyclization protocol, resulting in the construction of four new bonds and two ring moieties directly in one pot.

  8. Visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids to coumarin derivatives under metal-free conditions.

    PubMed

    Yang, Wenchao; Yang, Shuai; Li, Pinhua; Wang, Lei

    2015-05-01

    A visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids has been developed. The arylsulfonylation of alkynes was performed at room temperature under metal-free conditions to generate coumarin derivatives with wide functional group tolerance, good yields and high regioselectivity.

  9. Template-induced diverse metal-organic materials as catalysts for the tandem acylation-Nazarov cyclization.

    PubMed

    Huang, Chao; Ding, Ran; Song, Chuanjun; Lu, Jingjing; Liu, Lu; Han, Xiao; Wu, Jie; Hou, Hongwei; Fan, Yaoting

    2014-12-01

    In our continuing quest to develop a metal-organic framework (MOF)-catalyzed tandem pyrrole acylation-Nazarov cyclization reaction with α,β-unsaturated carboxylic acids for the synthesis of cyclopentenone[b]pyrroles, which are key intermediates in the synthesis of natural product (±)-roseophilin, a series of template-induced Zn-based (1-3) metal-organic frameworks (MOFs) have been solvothermally synthesized and characterized. Structural conversions from non-porous MOF 1 to porous MOF 2, and back to non-porous MOF 3 arising from the different concentrations of template guest have been observed. The anion-π interactions between the template guests and ligands could affect the configuration of ligands and further tailor the frameworks of 1-3. Futhermore, MOFs 1-3 have shown to be effective heterogeneous catalysts for the tandem acylation-Nazarov cyclization reaction. In particular, the unique structural features of 2, including accessible catalytic sites and suitable channel size and shape, endow 2 with all of the desired features for the MOF-catalyzed tandem acylation-Nazarov cyclization reaction, including heterogeneous catalyst, high catalytic activity, robustness, and excellent selectivity. A plausible mechanism for the catalytic reaction has been proposed and the structure-reactivity relationship has been further clarified. Making use of 2 as a heterogeneous catalyst for the reaction could greatly increase the yield of total synthesis of (±)-roseophilin. PMID:25303356

  10. Metal-Catalyzed Cyclization Reactions of 2,3,4-Trien-1-ols: A Joint Experimental-Computational Study.

    PubMed

    Alcaide, Benito; Almendros, Pedro; Cembellín, Sara; Fernández, Israel; Martínez Del Campo, Teresa

    2016-08-01

    Controlled preparation of tri- and tetrasubstituted furans, as well as carbazoles has been achieved through chemo- and regioselective metal-catalyzed cyclization reactions of cumulenic alcohols. The gold- and palladium-catalyzed cycloisomerization reactions of cumulenols, including indole-tethered 2,3,4-trien-1-ols, to trisubstituted furans was effective, due to a 5-endo-dig oxycyclization by attack of the hydroxy group onto the central cumulene double bond. In contrast, palladium-catalyzed heterocyclization/coupling reactions with 3-bromoprop-1-enes furnished tetrasubstituted furans. Also studied was the palladium-catalyzed cyclization/coupling sequence involving protected indole-tethered 2,3,4-trien-1-ols and 3-bromoprop-1-enes that exclusively generated trisubstituted carbazole derivatives. These results could be explained through a selective 6-endo-dig cumulenic hydroarylation, followed by aromatization. DFT calculations were carried out to understand this difference in reactivity. PMID:27383332

  11. Metal-Free Decarboxylative Cyclization/Ring Expansion: Construction of Five-, Six-, and Seven-Membered Heterocycles from 2-Alkynyl Benzaldehydes and Cyclic Amino Acids.

    PubMed

    Samala, Srinivas; Singh, Gajendra; Kumar, Ravi; Ampapathi, Ravi Sankar; Kundu, Bijoy

    2015-08-10

    A one pot synthesis of 1H-benzo[g]indoles, tetrahydrobenzo[h]quinolines, and naphtho[1,2-b]azepines from 2-alkynyl benzaldehydes and cyclic amino acids is reported. The salient feature of the strategy involves formation of three new bonds (one C-N and two C-C bonds) by a metal-free decarboxylation/cyclization/one-carbon ring expansion sequence in one pot. PMID:26148838

  12. NIS-catalyzed oxidative cyclization of alcohols with amidines: a simple and efficient transition-metal free method for the synthesis of 1,3,5-triazines.

    PubMed

    Tiwari, Abhishek R; T, Akash; Bhanage, Bhalchandra M

    2015-12-01

    An efficient method for the synthesis of 1,3,5-triazines by NIS-catalyzed oxidative cyclization of alcohols with amidines has been developed. The reaction works smoothly under transition-metal free and phosphine-free conditions to afford a wide range of 1,3,5-triazine derivatives in moderate to good yields. The synthetic methodology was achieved via in situ oxidation of alcohols to aldehydes. PMID:26477749

  13. Comparative experimental investigation on the actuation mechanisms of ionic polymer-metal composites with different backbones and water contents

    NASA Astrophysics Data System (ADS)

    Zhu, Zicai; Chang, Longfei; Asaka, Kinji; Wang, Yanjie; Chen, Hualing; Zhao, Hongxia; Li, Dichen

    2014-03-01

    Water-based ionic polymer-metal composites (IPMCs) exhibit complex deformation properties, especially when the water content changes. To explore the general actuation mechanisms, both Nafion and Flemion membranes are used as the polymer backbones. IPMC deformation includes three stages: fast anode deformation, relaxation deformation, and slow anode deformation, which is mainly dependent on the water content and the backbone. When the water content decreases from 21 to 14 wt. %, Nafion-IPMC exhibits a large negative relaxation deformation, zero deformation, a positive relaxation deformation, and a positive steady deformation without relaxation in sequence. Despite the slow anode deformation, Flemion-IPMC also shows a slight relaxation deformation, which disappears when the water content is less than 13 wt. %. The different water states are investigated at different water contents using nuclear magnetic resonance spectroscopy. The free water, which decreases rapidly at the beginning through evaporation, is proven to be critical for relaxation deformation. For the backbone, indirect evidence from the steady current response is correlated with the slow anode deformation of Flemion-IPMC. The latter is explained by the secondary dissociation of the weak acid group -COOH. Finally, we thoroughly explain not only the three deformations by swelling but also their evolvement with decreasing water content. A fitting model is also presented based on a multi-diffusion equation to reveal the deformation processes more clearly, the results from which are in good agreement with the experimental results.

  14. Comparative experimental investigation on the actuation mechanisms of ionic polymer–metal composites with different backbones and water contents

    SciTech Connect

    Zhu, Zicai; Chang, Longfei; Wang, Yanjie; Chen, Hualing; Asaka, Kinji; Zhao, Hongxia; Li, Dichen

    2014-03-28

    Water-based ionic polymer–metal composites (IPMCs) exhibit complex deformation properties, especially when the water content changes. To explore the general actuation mechanisms, both Nafion and Flemion membranes are used as the polymer backbones. IPMC deformation includes three stages: fast anode deformation, relaxation deformation, and slow anode deformation, which is mainly dependent on the water content and the backbone. When the water content decreases from 21 to 14 wt. %, Nafion–IPMC exhibits a large negative relaxation deformation, zero deformation, a positive relaxation deformation, and a positive steady deformation without relaxation in sequence. Despite the slow anode deformation, Flemion–IPMC also shows a slight relaxation deformation, which disappears when the water content is less than 13 wt. %. The different water states are investigated at different water contents using nuclear magnetic resonance spectroscopy. The free water, which decreases rapidly at the beginning through evaporation, is proven to be critical for relaxation deformation. For the backbone, indirect evidence from the steady current response is correlated with the slow anode deformation of Flemion-IPMC. The latter is explained by the secondary dissociation of the weak acid group –COOH. Finally, we thoroughly explain not only the three deformations by swelling but also their evolvement with decreasing water content. A fitting model is also presented based on a multi-diffusion equation to reveal the deformation processes more clearly, the results from which are in good agreement with the experimental results.

  15. Differentiating between fluorescence-quenching metal ions with polyfluorophore sensors built on a DNA backbone.

    PubMed

    Tan, Samuel S; Kim, Su Jeong; Kool, Eric T

    2011-03-01

    A common problem in detecting metal ions with fluorescentchemosensors is the emission-suppressing effects of fluorescence-quenching metal ions. This quenching tendency makes it difficult to design sensors with turn-on signal, and differentiate between several metal ions that may yield a strong quenching response. To address these challenges, we investigate a new sensor design strategy, incorporating fluorophores and metal ligands as DNA base replacements in DNA-like oligomers, for generating a broader range of responses for quenching metal ions. The modular molecular design enabled rapid synthesis and discovery of sensors from libraries on PEG-polystyrene beads. Using this approach, water-soluble sensors 1-5 were identified as strong responders to a set of eight typically quenching metal ions (Co(2+), Ni(2+), Cu(2+), Hg(2+), Pb(2+), Ag(+), Cr(3+), and Fe(3+)). They were synthesized and characterized for sensing responses in solution. Cross-screening with the full set of metal ions showed that they have a wide variety of responses, including emission enhancements and red- and blue-shifts. The diversity of sensor responses allows as few as two sensors (1 and 2) to be used together to successfully differentiate these eight metals. As a test, a set of unknown metal ion solutions in blind studies were also successfully identified based on the response pattern of the sensors. The modular nature of the sensor design strategy suggests a broadly applicable approach to finding sensors for differentiating many different cations by pattern-based recognition, simply by varying the sequence and composition of ligands and fluorophores on a DNA synthesizer.

  16. Pseudoprolines as removable turn inducers: tools for the cyclization of small peptides.

    PubMed

    Skropeta, Danielle; Jolliffe, Katrina A; Turner, Peter

    2004-12-10

    The cyclization of small peptides which do not incorporate turn inducers is often difficult. We have developed a method involving the use of removable turn inducers, in the form of pseudoprolines, for the cyclization of difficult peptide sequences. The pseudoprolines induce a cisoid amide bond in the peptide backbone which facilitates cyclization. They are then readily removed to yield a cyclic peptide that does not contain any turn inducers.

  17. Visible-Light-Mediated Generation of Nitrogen-Centered Radicals: Metal-Free Hydroimination and Iminohydroxylation Cyclization Reactions.

    PubMed

    Davies, Jacob; Booth, Samuel G; Essafi, Stephanie; Dryfe, Robert A W; Leonori, Daniele

    2015-11-16

    The formation and use of iminyl radicals in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O-aryl oximes. Owing to their low reduction potentials, the inexpensive organic dye eosin Y could be used as the photocatalyst of the organocatalytic hydroimination reaction. Furthermore, reaction conditions for a unique iminohydroxylation were identified; visible-light-mediated electron transfer from novel electron donor-acceptor complexes of the oximes and Et3N was proposed as a key step of this process.

  18. Non-Innocent Behavior of Substrate Backbone Esters in Metal-Catalyzed Carbocyclizations and Friedel-Crafts Reactions of Enynes and Arenynes.

    PubMed

    Michelet, Bastien; Thiery, Guillaume; Bour, Christophe; Gandon, Vincent

    2015-11-01

    On the basis of DFT computations and experimental results, we show that the presence of the ester group in the backbone of organic substrates can influence the mechanism of metal-catalyzed carbocyclization reactions. The non-innocent role of the ester functionality in lowering the activation barrier of the key step of the gallium- and indium-catalyzed cycloisomerization of 1,6-enynes is revealed. In the case of the gallium-catalyzed hydroarylation of arenynes, the esters in the tether can deprotonate the Wheland intermediate, thus avoiding more energetically demanding [1,3]- or [1,2]/[1,2]-H shifts. As for the gallium-catalyzed Friedel-Crafts alkylation, an unusual concerted SEAr mechanism involving the esters has been calculated. Lastly, computations evidence that the ester group of methyl propiolates enables a divergent mechanism in the platinum-catalyzed intramolecular hydroarylation. PMID:26448129

  19. Crosslinking metal nanoparticles into the polymer backbone of hydrogels enables preparation of soft, magnetic field-driven actuators with muscle-like flexibility.

    PubMed

    Fuhrer, Roland; Athanassiou, Evagelos Kimon; Luechinger, Norman Albert; Stark, Wendelin Jan

    2009-03-01

    The combination of force and flexibility is at the core of biomechanics and enables virtually all body movements in living organisms. In sharp contrast, presently used machines are based on rigid, linear (cylinders) or circular (rotator in an electrical engine) geometries. As a potential bioinspired alternative, magnetic elastomers can be realized through dispersion of micro- or nanoparticles in polymer matrices and have attracted significant interest as soft actuators in artificial organs, implants, and devices for controlled drug delivery. At present, magnetic particle loss and limited actuator strength have restricted the use of such materials to niche applications. We describe the direct incorporation of metal nanoparticles into the backbone of a hydrogel and application as an ultra-flexible, yet strong magnetic actuator. Covalent bonding of the particles prevents metal loss or leaching. Since metals have a far higher saturation magnetization and higher density than oxides, the resulting increased force/volume ratio afforded significantly stronger magnetic actuators with high mechanical stability, elasticity, and shape memory effect.

  20. Cross-coupling/cyclization reactions of two different allenic moieties.

    PubMed

    Alcaide, Benito; Almendros, Pedro; Martínez del Campo, Teresa

    2010-05-25

    The allene moiety represents an excellent building block for allene cross-coupling cyclization reactions, affording heterocyclic skeletons in a single step. This strategy is of particular interest when two different allene derivatives are involved in a series of metal-catalyzed cross-coupling heterocyclization processes. This Concept article is focused on the Pd-catalyzed union of two different allenic moieties, with cyclization of at least one of them by intramolecular cyclometalation. These new, versatile, and highly effective transformations are complex multistep processes leading to potential privileged structures that could find wide applications in related medicinal chemistry.

  1. Dicyclopropylmethyl peptide backbone protectant.

    PubMed

    Carpino, Louis A; Nasr, Khaled; Abdel-Maksoud, Adel Ali; El-Faham, Ayman; Ionescu, Dumitru; Henklein, Peter; Wenschuh, Holger; Beyermann, Michael; Krause, Eberhard; Bienert, Michael

    2009-08-20

    The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicyclopropylmethanimine hydrochloride with an amino acid ester followed by sodium cyanoborohydride or triacetoxyborohydride reduction, can be used as an amide bond protectant for peptide synthesis. Examples which demonstrate the amelioration of aggregation effects include syntheses of the alanine decapeptide and the prion peptide (106-126). Avoidance of cyclization to the aminosuccinimide followed substitution of Fmoc-(Dcpm)Gly-OH for Fmoc-Gly-OH in the assembly of sequences containing the sensitive Asp-Gly unit.

  2. SpyRing interrogation: analyzing how enzyme resilience can be achieved with phytase and distinct cyclization chemistries

    PubMed Central

    Schoene, Christopher; Bennett, S. Paul; Howarth, Mark

    2016-01-01

    Enzymes catalyze reactions with exceptional selectivity and rate acceleration but are often limited by instability. Towards a generic route to thermo-resilience, we established the SpyRing approach, cyclizing enzymes by sandwiching between SpyTag and SpyCatcher (peptide and protein partners which lock together via a spontaneous isopeptide bond). Here we first investigated the basis for this resilience, comparing alternative reactive peptide/protein pairs we engineered from Gram-positive bacteria. Both SnoopRing and PilinRing cyclization gave dramatic enzyme resilience, but SpyRing cyclization was the best. Differential scanning calorimetry for each ring showed that cyclization did not inhibit unfolding of the inserted β-lactamase. Cyclization conferred resilience even at 100 °C, where the cyclizing domains themselves were unfolded. Phytases hydrolyze phytic acid and improve dietary absorption of phosphate and essential metal ions, important for agriculture and with potential against human malnutrition. SpyRing phytase (PhyC) resisted aggregation and retained catalytic activity even following heating at 100 °C. In addition, SpyRing cyclization made it possible to purify phytase simply by heating the cell lysate, to drive aggregation of non-cyclized proteins. Cyclization via domains forming spontaneous isopeptide bonds is a general strategy to generate resilient enzymes and may extend the range of conditions for isolation and application of enzymes. PMID:26861173

  3. Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems.

    PubMed

    Itoh, Toshiyuki; Nokami, Toshiki; Kawatsura, Motoi

    2016-06-01

    Nazarov cyclization is an important and versatile method for the synthesis of five-membered carbocycles, and extensive studies have been conducted to optimize the reaction. Among recent studies, several trends are recognized. One is the combination of different reactions with Nazarov cyclization in a one-pot reaction system which enables the preparation of unique cyclization products. The second is the use of a transition-metal catalyst, though Lewis or Brønsted acids have generally been used for the reaction. The third is the realization of the asymmetric Nazarov cyclization. The fourth is the base-catalyzed Nazarov cyclization. Furthermore, several useful protocols for realizing Nazarov cyclization have also been developed. The recent progress on Nazarov cyclizations is summarized in Section 2. Section 3 is our chronicle in this field. We focused on the use of iron as the catalyst in Nazarov cyclizations and ionic liquids as solvents: Nazarov cyclization of thiophene derivatives using FeCl3 as the catalyst was accomplished and we succeeded in demonstrating the first example of an iron-catalyzed asymmetric Nazarov reaction. We next established Nazarov cyclization of pyrrole or indole derivatives using Fe(ClO4 )3 ·Al2 O3 as the catalyst with high trans selectivities in excellent yields. Since the cyclized product was reacted with a vinyl ketone in the presence of the same iron salt, the system allowed realization of the sequential type of Nazarov/Michael reaction of pyrrole derivatives. Furthermore, we demonstrated the recyclable use of the iron catalyst and obtained the desired Nazarov/Michael reaction products in good yields for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf2 ], as the solvent. We expect that the iron-catalyzed Nazarov cyclization, in particular, in an ionic liquid solvent might become a useful method to synthesize functional molecules that include cycloalkene moieties. PMID:27219324

  4. Biosynthetic Mechanism of Lanosterol: Cyclization.

    PubMed

    Chen, Nanhao; Wang, Shenglong; Smentek, Lidia; Hess, B Andes; Wu, Ruibo

    2015-07-20

    The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzed by oxidosqualene cyclase (OSC) has stimulated the interest of chemists and biologists for over a half century. Herein, the elaborate, state-of-the-art two-dimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves a nearly concerted, but highly asynchronous cyclization, to yield a stable intermediate with "6-6-5" rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the "6-6-6-5" protosterol cation. The calculated reaction barrier of the rate-limiting step (≈22 kcal mol(-1)) is comparable to the experimental kinetic results. Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism.

  5. Biosynthetic Mechanism of Lanosterol: Cyclization.

    PubMed

    Chen, Nanhao; Wang, Shenglong; Smentek, Lidia; Hess, B Andes; Wu, Ruibo

    2015-07-20

    The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzed by oxidosqualene cyclase (OSC) has stimulated the interest of chemists and biologists for over a half century. Herein, the elaborate, state-of-the-art two-dimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves a nearly concerted, but highly asynchronous cyclization, to yield a stable intermediate with "6-6-5" rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the "6-6-6-5" protosterol cation. The calculated reaction barrier of the rate-limiting step (≈22 kcal mol(-1)) is comparable to the experimental kinetic results. Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism. PMID:26069216

  6. Salen Promoted Enantioselective Nazarov Cyclizations of Activated and Unactivated Dienones

    PubMed Central

    2013-01-01

    A novel class of chiral 5,5′-di(2,4,6-trialkyl)aryl salen-metal complexes have been developed and shown to catalyze highly enantioselective Nazarov cyclization reactions, giving rise to cyclopentenoids in 90:10–98:2 er. Significantly, the catalysts also promote, for the first time, highly enantioselective Nazarov reactions of “unactivated” dienones, producing hydrindenone products having in place three contiguous chiral centers. PMID:23506509

  7. Organocatalyzed cyclizations of pi-allylpalladium complexes: a new method for the construction of five- and six-membered rings.

    PubMed

    Bihelovic, Filip; Matovic, Radomir; Vulovic, Bojan; Saicic, Radomir N

    2007-11-22

    Synergic combination of organotransition metal catalysis and organocatalysis allows, for the first time, the Tsuji-Trost cyclization of aldehydes. A catalytic asymmetric variant of the reaction is also possible. PMID:17958367

  8. Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence.

    PubMed

    Petersen, Rico; Cohrt, A Emil; Petersen, Michael Åxman; Wu, Peng; Clausen, Mads H; Nielsen, Thomas E

    2015-06-01

    Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.

  9. Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet-Spengler cyclization/metal-catalyzed cross coupling/amidation sequence.

    PubMed

    Petersen, Rico; Cohrt, A Emil; Petersen, Michael Åxman; Wu, Peng; Clausen, Mads H; Nielsen, Thomas E

    2015-06-01

    Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields. PMID:25703308

  10. Coarctate cyclization reactions: a primer.

    PubMed

    Young, Brian S; Herges, Rainer; Haley, Michael M

    2012-10-01

    The cleavage of five-membered heterocycles possessing an exocyclic carbene or nitrene to form conjugated ene-ene-yne systems has been documented for over 40 years; however, the reverse reaction, using a conjugated "ene-ene-yne" precursor to form a heterocycle is a relatively new approach. Over the past decade, the Haley and Herges groups have studied computationally and experimentally the cyclization of the "hetero-ene-ene-yne" motif via an unusual class of concerted reactions known as coarctate reactions. This feature article details our synthetic and mechanistic work involving triazene-arene-alkynes and structurally-related systems to generate heterocycles using coarctate chemistry.

  11. Emergence of terpene cyclization in Artemisia annua

    PubMed Central

    Salmon, Melissa; Laurendon, Caroline; Vardakou, Maria; Cheema, Jitender; Defernez, Marianne; Green, Sol; Faraldos, Juan A.; O’Maille, Paul E.

    2015-01-01

    The emergence of terpene cyclization was critical to the evolutionary expansion of chemical diversity yet remains unexplored. Here we report the first discovery of an epistatic network of residues that controls the onset of terpene cyclization in Artemisia annua. We begin with amorpha-4,11-diene synthase (ADS) and (E)-β-farnesene synthase (BFS), a pair of terpene synthases that produce cyclic or linear terpenes, respectively. A library of ~27,000 enzymes is generated by breeding combinations of natural amino-acid substitutions from the cyclic into the linear producer. We discover one dominant mutation is sufficient to activate cyclization, and together with two additional residues comprise a network of strongly epistatic interactions that activate, suppress or reactivate cyclization. Remarkably, this epistatic network of equivalent residues also controls cyclization in a BFS homologue from Citrus junos. Fitness landscape analysis of mutational trajectories provides quantitative insights into a major epoch in specialized metabolism. PMID:25644758

  12. Backbone dynamics in collagen

    NASA Astrophysics Data System (ADS)

    Aliev, Abil E.

    2004-11-01

    Peptide backbone motions of collagen have been extensively studied in the past. The experimental results were interpreted using a model of a collagen rod librating about its helix axis. Considering the size of the collagen molecule and the presence of cross-linked molecules, motional amplitudes derived for the helix axis libration were unusually high. Using solid-state NMR 13C chemical shift anisotropy and 2H quadrupolar lineshape analysis for five different isotope labelled collagens we show that motional averaging of the NMR interactions occurs primarily via small-angle librations about internal bond directions. This type of dynamics is compatible with both the presence of cross-links in collagen and the X-ray data, as well as dynamic models used for other proteins.

  13. Single Molecule Characterization of Conjugated Oligomers Formed through Radical Cyclization at a Surface

    NASA Astrophysics Data System (ADS)

    Tsai, Hsin-Zon; Riss, Alexander; Wickenburg, Sebastian; Tan, Liang; Gorman, Patrick; Oteyza, Dimas; Chen, Yen-Chia; Bradley, Aaron; Ugeda, Miguel; Etkin, Grisha; Louie, Steven; Fischer, Felix; Crommie, Michael

    2014-03-01

    Conjugated polymers have gained considerable attention due to their potential industrial applications and interesting fundamental properties. Real-space imaging their chemical bonds and understanding their electronic structures at the nanoscale could lead to enhanced control in the synthesis of these polymers for the potential applications in the nanoelectronics. Here, we present the synthesis and characterization of poly-acetylene derivatives resulting from cyclizations of enediyne molecules on an Au(111) surface. We performed non-contact atomic force microscopy (nc-AFM) with sub-molecular resolution to determine the precise chemical structure of cyclized monomers and chemically linked molecular chains. Additionally, STM measurements provide insight into the corresponding electronic structure and reveal a 1D conducting channel along the backbone of the conjugated oligomers, consistent with theoretical predictions. This work demonstrates the unique insight that can be gained by combining nc-AFM and STM to study the chemical and electronic structure of molecular assemblies at surfaces.

  14. Activation-Independent Cyclization of Monoterpenoids

    PubMed Central

    Siedenburg, Gabriele; Breuer, Michael; Juhl, Benjamin; Pleiss, Jürgen; Seitz, Miriam; Klebensberger, Janosch; Hauer, Bernhard

    2012-01-01

    The biosynthesis of cyclic monoterpenes (C10) generally requires the cyclization of an activated linear precursor (geranyldiphosphate) by specific terpene cyclases. Cyclic triterpenes (C30), on the other hand, originate from the linear precursor squalene by the action of squalene-hopene cyclases (SHCs) or oxidosqualene cyclases (OSCs). Here, we report a novel terpene cyclase from Zymomonas mobilis (ZMO1548-Shc) with the unique capability to cyclize citronellal to isopulegol. To our knowledge, ZMO1548-Shc is the first biocatalyst with diphosphate-independent monoterpenoid cyclase activity. A combinatorial approach using site-directed mutagenesis and modeling of the active site with a bound substrate revealed that the cyclization of citronellal proceeds via a different mechanism than that of the cyclization of squalene. PMID:22156419

  15. Activation-independent cyclization of monoterpenoids.

    PubMed

    Siedenburg, Gabriele; Jendrossek, Dieter; Breuer, Michael; Juhl, Benjamin; Pleiss, Jürgen; Seitz, Miriam; Klebensberger, Janosch; Hauer, Bernhard

    2012-02-01

    The biosynthesis of cyclic monoterpenes (C(10)) generally requires the cyclization of an activated linear precursor (geranyldiphosphate) by specific terpene cyclases. Cyclic triterpenes (C(30)), on the other hand, originate from the linear precursor squalene by the action of squalene-hopene cyclases (SHCs) or oxidosqualene cyclases (OSCs). Here, we report a novel terpene cyclase from Zymomonas mobilis (ZMO1548-Shc) with the unique capability to cyclize citronellal to isopulegol. To our knowledge, ZMO1548-Shc is the first biocatalyst with diphosphate-independent monoterpenoid cyclase activity. A combinatorial approach using site-directed mutagenesis and modeling of the active site with a bound substrate revealed that the cyclization of citronellal proceeds via a different mechanism than that of the cyclization of squalene. PMID:22156419

  16. Activation-independent cyclization of monoterpenoids.

    PubMed

    Siedenburg, Gabriele; Jendrossek, Dieter; Breuer, Michael; Juhl, Benjamin; Pleiss, Jürgen; Seitz, Miriam; Klebensberger, Janosch; Hauer, Bernhard

    2012-02-01

    The biosynthesis of cyclic monoterpenes (C(10)) generally requires the cyclization of an activated linear precursor (geranyldiphosphate) by specific terpene cyclases. Cyclic triterpenes (C(30)), on the other hand, originate from the linear precursor squalene by the action of squalene-hopene cyclases (SHCs) or oxidosqualene cyclases (OSCs). Here, we report a novel terpene cyclase from Zymomonas mobilis (ZMO1548-Shc) with the unique capability to cyclize citronellal to isopulegol. To our knowledge, ZMO1548-Shc is the first biocatalyst with diphosphate-independent monoterpenoid cyclase activity. A combinatorial approach using site-directed mutagenesis and modeling of the active site with a bound substrate revealed that the cyclization of citronellal proceeds via a different mechanism than that of the cyclization of squalene.

  17. The "universal polymer backbone" concept

    NASA Astrophysics Data System (ADS)

    Pollino, Joel Matthew

    This thesis begins with a brief analysis of the synthetic methodologies utilized in polymer science. A conclusion is drawn inferring that upper limits in molecular design are inevitable, arising as a direct consequence of the predominance of covalent strategies in the field. To address these concerns, the 'universal polymer backbone' (UPB) concept has been hypothesized. A UPB has been defined as any copolymer, side-chain functionalized with multiple recognition elements that are individually capable of forming strong, directional, and reversible non-covalent bonds. Non-covalent functionalization of these scaffolds can lead to the formation of a multitude of new polymer structures, each stemming from a single parent or 'universal polymer backbone'. To prepare such a UPB, isomerically pure exo-norbornene esters containing either a PdII SCS pincer complex or a diaminopyridine residue were synthesized, polymerized, and copolymerized via ROMP. All polymerizations were living under mild reaction conditions. Kinetic studies showed that the kp values are highly dependent upon the isomeric purity but completely independent of the terminal recognition units. Non-covalent functionalization of these copolymers was accomplished via (1) directed self-assembly, (2) multi-step self-assembly , and (3) one-step orthogonal self-assembly. This system shows complete specificity of each recognition motif for its complementary unit with no observable changes in the association constant upon functionalization. To explore potential applications of this UPB concept, random terpolymers possessing high concentrations of pendant alkyl chains and small amounts of recognition units were synthesized. Non-covalent crosslinking using a directed functionalization strategy resulted in dramatic increases in solution viscosities for metal crosslinked polymers with only minor changes in viscosity for hydrogen bonding motifs. The crosslinked materials were further functionalized via self-assembly by

  18. Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions.

    PubMed

    Desrosiers, Jean-Nicolas; Hie, Liana; Biswas, Soumik; Zatolochnaya, Olga V; Rodriguez, Sonia; Lee, Heewon; Grinberg, Nelu; Haddad, Nizar; Yee, Nathan K; Garg, Neil K; Senanayake, Chris H

    2016-09-19

    A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis. PMID:27600647

  19. Reversible Bergman cyclization by atomic manipulation

    NASA Astrophysics Data System (ADS)

    Schuler, Bruno; Fatayer, Shadi; Mohn, Fabian; Moll, Nikolaj; Pavliček, Niko; Meyer, Gerhard; Peña, Diego; Gross, Leo

    2016-03-01

    The Bergman cyclization is one of the most fascinating rearrangements in chemistry, with important implications in organic synthesis and pharmacology. Here we demonstrate a reversible Bergman cyclization for the first time. We induced the on-surface transformation of an individual aromatic diradical into a highly strained ten-membered diyne using atomic manipulation and verified the products by non-contact atomic force microscopy with atomic resolution. The diyne and diradical were stabilized by using an ultrathin NaCl film as the substrate, and the diyne could be transformed back into the diradical. Importantly, the diradical and the diyne exhibit different reactivity, electronic, magnetic and optical properties associated with the changes in the bond topology, and spin multiplicity. With this reversible, triggered Bergman cyclization we demonstrated switching on demand between the two reactive intermediates by means of selective C-C bond formation or cleavage, which opens up the field of radical chemistry for on-surface reactions by atomic manipulation.

  20. Practical Radical Cyclizations with Arylboronic Acids and Trifluoroborates

    PubMed Central

    Lockner, Jonathan W.; Dixon, Darryl D.; Risgaard, Rune; Baran, Phil S.

    2011-01-01

    Practical radical cyclizations using organoboronic acids and trifluoroborates take place in water, open to air, and in a scalable fashion employing catalytic silver nitrate and stoichiometric potassium persulfate. Both Pschorr-type cyclizations and tandem radical cyclization/trap cascades are described, illustrating the utility of these mild conditions for the generation of polycyclic scaffolds. PMID:21923108

  1. Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues.

    PubMed

    Schumann, C; Seyfarth, L; Greiner, G; Paegelow, I; Reissmann, S

    2002-08-01

    A series of conformationally constrained cyclic analogues of the peptide hormone bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) was synthesized to check different turned structures proposed for the bioactive conformation of BK agonists and antagonists. Cycles differing in the size and direction of the lactam bridge were performed at the C- and N-terminal sequences of the molecule. Glutamic acid and lysine were introduced into the native BK sequence at different positions for cyclization through their side chains. Backbone cyclic analogues were synthesized by incorporation of N-carboxy alkylated and N-amino alkylated amino acids into the peptide chain. Although the coupling of Fmoc-glycine to the N-alkylated phenylalanine derivatives was effected with DIC/HOAt in SPPS, the dipeptide building units with more bulky amino acids were pre-built in solution. For backbone cyclization at the C-terminus an alternative building unit with an acylated reduced peptide bond was preformed in solution. Both types of building units were handled in the SPPS in the same manner as amino acids. The agonistic and antagonistic activities of the cyclic BK analogues were determined in rat uterus (RUT) and guinea-pig ileum (GPI) assays. Additionally, the potentiation of the BK-induced effects was examined. Among the series of cyclic BK agonists only compound 3 with backbone cyclization between positions 2 and 5 shows a significant agonistic activity on RUT. To study the influence of intramolecular ring closure we used an antagonistic analogue with weak activity, [D-Phe7]-BK. Side chain as well as backbone cyclization in the N-terminus of [D-Phe7]-BK resulted in analogues with moderate antagonistic activity on RUT. Also, compound 18 in which a lactam bridge between positions 6 and 9 was achieved via an acylated reduced peptide bond has moderate antagonistic activity on RUT. These results support the hypothesis of turn structures in both parts of the molecule as a requirement for BK

  2. ANSS Backbone Station Quality Assessment

    NASA Astrophysics Data System (ADS)

    Leeds, A.; McNamara, D.; Benz, H.; Gee, L.

    2006-12-01

    In this study we assess the ambient noise levels of the broadband seismic stations within the United States Geological Survey's (USGS) Advanced National Seismic System (ANSS) backbone network. The backbone consists of stations operated by the USGS as well as several regional network stations operated by universities. We also assess the improved detection capability of the network due to the installation of 13 additional backbone stations and the upgrade of 26 existing stations funded by the Earthscope initiative. This assessment makes use of probability density functions (PDF) of power spectral densities (PSD) (after McNamara and Buland, 2004) computed by a continuous noise monitoring system developed by the USGS- ANSS and the Incorporated Research Institutions in Seismology (IRIS) Data Management Center (DMC). We compute the median and mode of the PDF distribution and rank the stations relative to the Peterson Low noise model (LNM) (Peterson, 1993) for 11 different period bands. The power of the method lies in the fact that there is no need to screen the data for system transients, earthquakes or general data artifacts since they map into a background probability level. Previous studies have shown that most regional stations, instrumented with short period or extended short period instruments, have a higher noise level in all period bands while stations in the US network have lower noise levels at short periods (0.0625-8.0 seconds), high frequencies (8.0- 0.125Hz). The overall network is evaluated with respect to accomplishing the design goals set for the USArray/ANSS backbone project which were intended to increase broadband performance for the national monitoring network.

  3. The backbone of a city

    NASA Astrophysics Data System (ADS)

    Scellato, S.; Cardillo, A.; Latora, V.; Porta, S.

    2006-03-01

    Recent studies have revealed the importance of centrality measures to analyze various spatial factors affecting human life in cities. Here we show how it is possible to extract the backbone of a city by deriving spanning trees based on edge betweenness and edge information. By using as sample cases the cities of Bologna and San Francisco, we show how the obtained trees are radically different from those based on edge lengths, and allow an extended comprehension of the “skeleton” of most important routes that so much affects pedestrian/vehicular flows, retail commerce vitality, land-use separation, urban crime and collective dynamical behaviours.

  4. Ruthenium-Catalyzed Hydroalkynylative Cyclization of 1,6-Enynes Induced by Substituent Effects.

    PubMed

    Liu, Rui; Ni, Zhenjie; Giordano, Laurent; Tenaglia, Alphonse

    2016-08-19

    The ruthenium-catalyzed 1,6-enyne cyclization in the presence of bulky substituted terminal alkyne proceeds smoothly at room temperature to afford highly substituted five-membered cyclic compounds featuring a 1,5-enyne motif. Deuterium-labeling experiments showed that the key ruthenacyclopentene intermediate undergoes cleavage of metal-carbon bonds through the metal-assisted σ-bond metathesis reaction, thus leading to the formation of C(sp(2))-H and C(sp(3))-C(sp) bonds. PMID:27504966

  5. Peptide and peptide library cyclization via bromomethylbenzene derivatives.

    PubMed

    Hacker, David E; Almohaini, Mohammed; Anbazhagan, Aruna; Ma, Zhong; Hartman, Matthew C T

    2015-01-01

    Cyclization confers several advantages to peptides, cumulatively serving to make them more drug-like. In this protocol, cyclic peptides are generated via bis-alkylation of cysteine-containing peptides using α,α'-dibromo-m-xylene. The reactions are robust and high yielding. Multiple reaction platforms for the application of this versatile strategy are described herein: the cyclization of solid-phase-synthesized peptides, both in solution and on resin, as well as the cyclization of in vitro translated mRNA-peptide fusion libraries on oligo(dT) resin.

  6. New modes for the osmium-catalyzed oxidative cyclization.

    PubMed

    Donohoe, Timothy J; Lindsay-Scott, Peter J; Parker, Jeremy S; Callens, Cedric K A

    2010-03-01

    The osmium-catalyzed oxidative cyclization of amino alcohol initiators formally derived from 1,4-dienes is an effective method for the construction of pyrrolidines, utilizing a novel reoxidant (4-nitropyridine N-oxide = NPNO). The cyclization of enantiopure syn- and anti-amino alcohols gives rise to enantiopure cis- and trans-2,5-disubstituted pyrrolidines, respectively. Moreover, the cyclization of bis-homoallylic amines bearing an exocyclic chelating group is shown to be a complementary method for trans-pyrrolidine formation.

  7. "Click"-cyclized (68)Ga-labeled peptides for molecular imaging and therapy: synthesis and preliminary in vitro and in vivo evaluation in a melanoma model system.

    PubMed

    Martin, Molly E; Sue O'Dorisio, M; Leverich, Whitney M; Kloepping, Kyle C; Walsh, Susan A; Schultz, Michael K

    2013-01-01

    Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disulfide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In the work described in this chapter, new α-melanocyte stimulating hormone (α-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition "click" chemistry techniques. The α-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represent a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor-bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) for MC1R on melanoma cells in vitro, high stability in human serum, and produced high-contrast PET/CT images of tumor xenografts. (68)Ga-labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor-mediated tumor accumulation of up to 16 ± 5% ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radio metals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy.

  8. Short and stereoselective total synthesis of furano lignans (+/-)-dihydrosesamin, (+/-)-lariciresinol dimethyl ether, (+/-)-acuminatin methyl ether, (+/-)-sanshodiol methyl ether, (+/-)-lariciresinol, (+/-)-acuminatin, and (+/-)-lariciresinol monomethyl ether and furofuran lignans (+/-)-sesamin, (+/-)-eudesmin, (+/-)-piperitol methyl ether, (+/-)-pinoresinol, (+/-)-piperitol, and (+/-)-pinoresinol monomethyl ether by radical cyclization of epoxides using a transition-metal radical source.

    PubMed

    Roy, Subhas Chandra; Rana, Kalyan Kumar; Guin, Chandrani

    2002-05-17

    Intramolecular radical cyclization of suitably substituted epoxy ethers 4a-g using bis(cyclopentadienyl)titanium(III) chloride as the radical source resulted in trisubstituted tetrahydrofurano lignans and 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans depending on the reaction conditions. The titanium(III) species was prepared in situ from commercially available titanocene dichloride and activated zinc dust in THF. Upon radical cyclization followed by acidic workup, epoxy olefinic ethers 4a-g afforded furano lignans dihydrosesamin 1a, lariciresinol dimethyl ether 1b, acuminatin methyl ether 1e, and sanshodiol methyl ether 1g directly and lariciresinol 1h, acuminatin 1i, and lariciresinol monomethyl ether 1j after removal of the benzyl protecting group by controlled hydrogenolysis of the corresponding cyclized products. The furofuran lignans sesamin 2a, eudesmin 2b, and piperitol methyl ether 2e were also prepared directly by using the same precursors 4a-f on radical cyclization followed by treatment with iodine and pinoresinol 2h, piperitol 2i, and pinoresinol monomethyl ether 2j after controlled hydrogenolysis of the benzyl protecting group of the corresponding cyclized products. Two naturally occurring acyclic lignans, secoisolariciresinol 5h and secoisolariciresinol dimethyl ether 5b, have also been prepared by exhaustive hydrogenolysis of 2h and 2b, respectively.

  9. Photomodulation of conformational states. II. Mono- and bicyclic peptides with (4-aminomethyl)phenylazobenzoic acid as backbone constituent.

    PubMed

    Renner, C; Cramer, J; Behrendt, R; Moroder, L

    2000-12-01

    It has been reported that backbone cyclization of octapeptides with the photoresponsive (4-aminomethyl)phenylazobenzoic acid imparts sufficient restraints to induce and stabilize ordered conformations of the peptide backbone in both the cis- and trans-azo-isomers (L. Ulysse, J. Cubillos, and J. Chmielewski, Journal of the American Chemical Society, 1995, Vol. 117, pp. 8466-8467). Correspondingly, the active-site octapeptide fragment H-Ala-Cys-Ala-Thr-Cys-Asp-Gly-Phe-OH [134-141] of thioredoxin reductase, with its high preference for a 3(10)-helix turn conformation centered on the Thr-Cys sequence, was backbone cyclized with this azobenzene moiety in the attempt to design a photoresponsive system where the conformational states of the peptide backbone are dictated by the configuration of the azobenzene and can be further modulated by the disulfide bridge. Nuclear magnetic resonance conformational analysis of the monocyclic compound clearly revealed the presence of two conformational families in both the cis- and trans-azo configuration. Of the higher populated conformational families, the structure of the trans-isomer seems like a pretzel-like folding, while the cis-isomer relaxes into a significantly less defined conformational state that does not exhibit any regular structural elements. Further restrictions imparted by disulfide bridging of the peptide moiety leads to an even better defined conformation for the trans-azo-isomer, whereas the cis-isomer can be described as a frustrated system without pronounced energy minima and thus with little conformational preferences. Our findings would suggest that this photoresponsive peptide template may not be of general usefulness for light-induced conformational transitions between two well-defined conformational states at least under the experimental conditions employed, even in the bicyclic form. However, trans --> cis isomerization of the bicyclic peptide is accompanied by a switch from a well-defined conformation to

  10. External Tank - The Structure Backbone

    NASA Technical Reports Server (NTRS)

    Welzyn, Kenneth; Pilet, Jeffrey C.; Diecidue-Conners, Dawn; Worden, Michelle; Guillot, Michelle

    2011-01-01

    The External Tank forms the structural backbone of the Space Shuttle in the launch configuration. Because the tank flies to orbital velocity with the Space Shuttle Orbiter, minimization of weight is mandatory, to maximize payload performance. Choice of lightweight materials both for structure and thermal conditioning was necessary. The tank is large, and unique manufacturing facilities, tooling, handling, and transportation operations were required. Weld processes and tooling evolved with the design as it matured through several block changes, to reduce weight. Non Destructive Evaluation methods were used to assure integrity of welds and thermal protection system materials. The aluminum-lithium alloy was used near the end of the program and weld processes and weld repair techniques had to be refined. Development and implementation of friction stir welding was a substantial technology development incorporated during the Program. Automated thermal protection system application processes were developed for the majority of the tank surface. Material obsolescence was an issue throughout the 40 year program. The final configuration and tank weight enabled international space station assembly in a high inclination orbit allowing international cooperation with the Russian Federal Space Agency. Numerous process controls were implemented to assure product quality, and innovative proof testing was accomplished prior to delivery. Process controls were implemented to assure cleanliness in the production environment, to control contaminants, and to preclude corrosion. Each tank was accepted via rigorous inspections, including non-destructive evaluation techniques, proof testing, and all systems testing. In the post STS-107 era, the project focused on ascent debris risk reduction. This was accomplished via stringent process controls, post flight assessment using substantially improved imagery, and selective redesigns. These efforts were supported with a number of test programs to

  11. Gold-catalyzed cyclization reactions of allenol and alkynol derivatives.

    PubMed

    Alcaide, Benito; Almendros, Pedro

    2014-03-18

    Although gold is chemically inert as a bulk metal, the landmark discovery that gold nanoparticles can be effective catalysts has opened up new and exciting research opportunities in the field. In recent years, there has been growth in the number of reactions catalyzed by gold complexes [gold(I) and gold(III)], usually as homogeneous catalysts, because they are soft Lewis acids. In addition, alkynes and allenes have interesting reactivities and selectivities, notably their ability to produce complex structures in very few steps. In this Account, we describe our work in gold catalysis with a focus on the formation of C-C and C-O bonds using allenes and alkynes as starting materials. Of these, oxa- and carbo-cyclizations are perhaps the best known and most frequently studied. We have divided those contributions into sections arranged according to the nature of the starting material (allene versus alkyne). Gold-catalyzed carbocyclizations in allenyl C2-linked indoles, allenyl-β-lactams, and allenyl sugars follow different mechanistic pathways. The cyclization of indole-tethered allenols results in the efficient synthesis of carbazole derivatives, for example. However, the compound produced from gold-catalyzed 9-endo carbocyclization of (aryloxy)allenyl-tethered 2-azetidinones is in noticeable contrast to the 5-exo hydroalkylation product that results from allenyl sugars. We have illustrated the unusual preference for the 4-exo-dig cyclization in allene chemistry, as well as the rare β-hydride elimination reaction, in gold catalysis from readily available α-allenols. We have also observed in γ-allenols that a (methoxymethyl)oxy protecting group not only masks a hydroxyl functionality but also exerts directing effects as a controlling unit in a gold-catalyzed regioselectivity reversal. Our recent work has also led to a combined experimental and computational study on regioselective gold-catalyzed synthetic routes to 1,3-oxazinan-2-ones (kinetically controlled

  12. Exercise: The Backbone of Spine Treatment

    MedlinePlus

    Exercise: The Backbone of Spine Treatment | View Video Back About Video Struggling with Low Back Pain? Many people are surprised to learn that carefully selected exercise can actually reduce back pain. Some exercises can ...

  13. Structural determinants of reductive terpene cyclization in iridoid biosynthesis.

    PubMed

    Kries, Hajo; Caputi, Lorenzo; Stevenson, Clare E M; Kamileen, Mohammed O; Sherden, Nathaniel H; Geu-Flores, Fernando; Lawson, David M; O'Connor, Sarah E

    2016-01-01

    The carbon skeleton of ecologically and pharmacologically important iridoid monoterpenes is formed in a reductive cyclization reaction unrelated to canonical terpene cyclization. Here we report the crystal structure of the recently discovered iridoid cyclase (from Catharanthus roseus) bound to a mechanism-inspired inhibitor that illuminates substrate binding and catalytic function of the enzyme. Key features that distinguish iridoid synthase from its close homolog progesterone 5β-reductase are highlighted.

  14. Enantioselective Nazarov Cyclization Catalyzed by a Cinchona Alkaloid Derivative

    PubMed Central

    Huang, Yu-Wen; Frontier, Alison J.

    2015-01-01

    Nucleophilic catalysts for a 1,6 addition/Nazarov cyclization/elimination sequence were evaluated for their ability to induce enantioselectivity in the electrocyclization step. Of the tertiary amines examined, it was found that a cinchona alkaloid derivative was able to generate substituted 5-hydroxy γ-methylene cyclopentenones with excellent enantioselectivity. The study results suggest that successful cyclization depends upon the ability of the dienyl diketone substrate to readily adopt an s-cis conformation. PMID:26085696

  15. A Light-Induced Vinylogous Nazarov-Type Cyclization.

    PubMed

    Pusch, Stefan; Schollmeyer, Dieter; Opatz, Till

    2016-07-01

    The first examples of a photochemically induced vinylogous Nazarov-type cyclization forming a cycloheptadienone core are described. The reaction can be included in a three-step cascade consisting of a photochemical isoxazole-azirine ring contraction, cobalt(II)-catalyzed ring expansion, and the photochemical cyclization. Furthermore, the first representative of the hitherto unknown 1-azatricyclo[2.2.0.0(2,6)]hexanes has been identified as a side product of the azirine formation. PMID:27281651

  16. Structural determinants of reductive terpene cyclization in iridoid biosynthesis

    PubMed Central

    Stevenson, Clare E. M.; Kamileen, Mohammed O.; Sherden, Nathaniel H.; Geu-Flores, Fernando; Lawson, David M.; O’Connor, Sarah E.

    2015-01-01

    The carbon skeleton of ecologically and pharmacologically important iridoid monoterpenes is formed in a reductive cyclization reaction unrelated to canonical terpene cyclization. Here we report the crystal structure of the recently discovered iridoid cyclase (Catharanthus roseus) bound to a mechanism-inspired inhibitor that illuminates substrate binding and catalytic function of the enzyme. Key features that distinguish iridoid synthase from its close homologue, progesterone 5β-reductase, are highlighted. PMID:26551396

  17. Electrophilic Carbonyl Activation: Competing Condensative Cyclizations of Tryptamine Derivatives

    PubMed Central

    Liu, Fan; Movassaghi, Mohammad

    2014-01-01

    A series of tryptamine derived bisindole substrates were subject to electrophilic activation of the functional grouping at their alpha-nitrogen in the form of iminium ions to enable cyclization onto the sterically hindered indole substructure. Our observations regarding divergent cyclization outcomes using electronically distinct bisindole substrates are described. Surprising preference for Friedel-Crafts alkylation reaction and evidence for an intriguing reversible spirocyclization are discussed. PMID:26120209

  18. Cetalox and analogues: synthesis via acid-mediated polyene cyclizations.

    PubMed

    Snowden, Roger L

    2008-06-01

    Using a novel, acid-mediated cyclization methodology, a direct access to Cetalox ((+/-)-1; a commercially important ambergris-type odorant) and various structurally related didehydro (i.e., 19, 26, and 30) and tetradehydro (i.e., 28 and 37/38) analogues is described. Treatment of either (E,E)-14 or (E)-15 with an excess of FSO(3)H in 2-nitropropane at -90 degrees stereospecifically afforded (+/-)-1 in 40 and 42% yield, respectively. Under similar conditions, cyclization of (E)-18 or 20 furnished 19 in 60 and 64% yield, respectively. Analogously, using an excess of ClSO(3)H in CH(2)Cl(2) at -80 degrees, 26 is formed with high stereoselectivity by cyclization of either (E)-24 or (Z)-25 (52 and 31% yield, resp.); in the same manner, 28 was prepared from 27 (22% yield). The same principle was applied to the synthesis of racemic Superambrox (30), via cyclization of 35, but only with poor selectivity (22%) and low yield (7%). Another approach via cyclization of (E)-40 under solvolysis conditions (excess TFA in CH(2)Cl(2) at -10 degrees) gave a higher yield (15%) with improved selectivity (43%). Finally, cyclization of 34 (1:1 diastereoisomer mixture) afforded 37/38 (10:1) in 27% yield. The qualitative organoleptic properties of 19, 26, 28, 30, and 37/38 (10:1) are briefly discussed.

  19. Cyclization Issues in Silicon-Containing Hyperbranched Polymers

    NASA Astrophysics Data System (ADS)

    Son, David Y.

    Theoretical descriptions of ABn (n ≥ 2) hyperbranched polymerization systems have been known for some time [1], but in them, cyclization is a factor that is generally and largely ignored. However, it is now understood that cyclization is prevalent in polymerizations of this type, and that it can often affect to a significant extent both polydispersity and molecular weights of the polymer products. Since research in hyperbranched polymers has increased dramatically in recent years [2-4], a number of experimental and theoretical studies have focused on the presence and effects of cyclization in these systems (see, for example [5-10] and references cited therein). In essence, intramolecular cyclization of an oligomer in an ABn polymerization results in the consumption of the focal A group (see Section 15.3), which converts the oligomer into a Bx core. Although the newly formed core can continue to grow through the reaction of other A groups with the B groups, this growth is limited, especially if other A groups in the polymerization system are also consumed through similar intramolecular cyclization reactions. Thus, for the control and optimization of the resulting polymer molecular weight, it is necessary to understand these issues and the methods that can be used to avoid excessive amounts of cyclization

  20. Direct synthesis of sulfonated dihydroisoquinolinones from N-allylbenzamide and arylsulfinic acids via TBHP-promoted cascade radical addition and cyclization.

    PubMed

    Xia, Dong; Li, Yang; Miao, Tao; Li, Pinhua; Wang, Lei

    2016-10-01

    A novel synthesis of sulfonated dihydroisoquinolinones via cascade radical addition and cyclization was developed in the presence of tert-butyl hydroperoxide (TBHP). The reactions generated the desired sulfonated dihydroisoquinolinones in good yields from readily available arylsulfinic acids and N-allylbenzamides under metal-free conditions. PMID:27604055

  1. Understanding traffic dynamics at a backbone POP

    NASA Astrophysics Data System (ADS)

    Taft, Nina; Bhattacharyya, Supratik; Jetcheva, Jorjeta; Diot, Christophe

    2001-07-01

    Spatial and temporal information about traffic dynamics is central to the design of effective traffic engineering practices for IP backbones. In this paper we study backbone traffic dynamics using data collected at a major POP on a tier-1 IP backbone. We develop a methodology that combines packet-level traces from access links in the POP and BGP routing information to build components of POP-to-POP traffic matrices. Our results show that there is wide disparity in the volume of traffic headed towards different egress POPs. At the same time, we find that current routing practices in the backbone tend to constrain traffic between ingress-egress POP pairs to a small number of paths. As a result, there is a wide variation in the utilization level of links in the backbone. Frequent capacity upgrades of the heavily used links are expensive; the need for such upgrades can be reduced by designing load balancing policies that will route more traffic over less utilized links. We identify traffic aggregates based on destination address prefixes and find that this set of criteria isolates a few aggregates that account for an overwhelmingly large portion of inter-POP traffic. We also demonstrate that these aggregates exhibit stability throughout the day on per-hour time scales, and thus they form a natural basis for splitting traffic over multiple paths in order to improve load balancing.

  2. The Dicyclopropylmethyl (Dcpm) Peptide Backbone Protectant†

    PubMed Central

    Carpino, Louis A.; Nasr, Khaled; Abdel-Maksoud, Adel Ali; El-Faham, Ayman; Ionescu, Dumitru; Henklein, Peter; Wenschuh, Holger; Beyermann, Michael; Krause, Eberhard; Bienert, Michael

    2009-01-01

    The N-dicyclopropylmethyl (Dcpm) residue, introduced into amino acids via reaction of dicyclopropylmethanimine hydrochloride with an amino acid ester followed by sodium cyanoborohydride or triacetoxyborohydride reduction, can be used as an amide bond protectant for peptide synthesis. Examples which demonstrate the amelioration of aggregation effects include syntheses of the alanine decapeptide and the prion peptide (106–126). Avoidance of cyclization to the aminosuccinimide followed substitution of Fmoc-(Dcpm)Gly-OH for Fmoc-Gly-OH in the assembly of sequences containing the sensitive Asp-Gly unit. PMID:19719204

  3. Discovery of cyclotides in the fabaceae plant family provides new insights into the cyclization, evolution, and distribution of circular proteins.

    PubMed

    Poth, Aaron G; Colgrave, Michelle L; Philip, Reynold; Kerenga, Bomai; Daly, Norelle L; Anderson, Marilyn A; Craik, David J

    2011-04-15

    Cyclotides are plant proteins whose defining structural features are a head-to-tail cyclized backbone and three interlocking disulfide bonds, which in combination are known as a cyclic cystine knot. This unique structural motif confers cyclotides with exceptional resistance to proteolysis. Their endogenous function is thought to be as plant defense agents, associated with their insecticidal and larval growth-inhibitory properties. However, in addition, an array of pharmaceutically relevant biological activities has been ascribed to cyclotides, including anti-HIV, anthelmintic, uterotonic, and antimicrobial effects. So far, >150 cyclotides have been elucidated from members of the Rubiaceae, Violaceae, and Cucurbitaceae plant families, but their wider distribution among other plant families remains unclear. Clitoria ternatea (Butterfly pea) is a member of plant family Fabaceae and through its usage in traditional medicine to aid childbirth bears similarity to Oldenlandia affinis, from which many cyclotides have been isolated. Using a combination of nanospray and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) analyses, we examined seed extracts of C. ternatea and discovered cyclotides in the Fabaceae, the third-largest family of flowering plants. We characterized 12 novel cyclotides, thus expanding knowledge of cyclotide distribution and evolution within the plant kingdom. The discovery of cyclotides containing novel sequence motifs near the in planta cyclization site has provided new insights into cyclotide biosynthesis. In particular, MS analyses of the novel cyclotides from C. ternatea suggest that Asn to Asp variants at the cyclization site are more common than previously recognized. Moreover, this study provides impetus for the examination of other economically and agriculturally significant species within Fabaceae, now the largest plant family from which cyclotides have been described. PMID:21194241

  4. Discovery of cyclotides in the fabaceae plant family provides new insights into the cyclization, evolution, and distribution of circular proteins.

    PubMed

    Poth, Aaron G; Colgrave, Michelle L; Philip, Reynold; Kerenga, Bomai; Daly, Norelle L; Anderson, Marilyn A; Craik, David J

    2011-04-15

    Cyclotides are plant proteins whose defining structural features are a head-to-tail cyclized backbone and three interlocking disulfide bonds, which in combination are known as a cyclic cystine knot. This unique structural motif confers cyclotides with exceptional resistance to proteolysis. Their endogenous function is thought to be as plant defense agents, associated with their insecticidal and larval growth-inhibitory properties. However, in addition, an array of pharmaceutically relevant biological activities has been ascribed to cyclotides, including anti-HIV, anthelmintic, uterotonic, and antimicrobial effects. So far, >150 cyclotides have been elucidated from members of the Rubiaceae, Violaceae, and Cucurbitaceae plant families, but their wider distribution among other plant families remains unclear. Clitoria ternatea (Butterfly pea) is a member of plant family Fabaceae and through its usage in traditional medicine to aid childbirth bears similarity to Oldenlandia affinis, from which many cyclotides have been isolated. Using a combination of nanospray and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) analyses, we examined seed extracts of C. ternatea and discovered cyclotides in the Fabaceae, the third-largest family of flowering plants. We characterized 12 novel cyclotides, thus expanding knowledge of cyclotide distribution and evolution within the plant kingdom. The discovery of cyclotides containing novel sequence motifs near the in planta cyclization site has provided new insights into cyclotide biosynthesis. In particular, MS analyses of the novel cyclotides from C. ternatea suggest that Asn to Asp variants at the cyclization site are more common than previously recognized. Moreover, this study provides impetus for the examination of other economically and agriculturally significant species within Fabaceae, now the largest plant family from which cyclotides have been described.

  5. Terpene cyclization catalysed inside a self-assembled cavity

    NASA Astrophysics Data System (ADS)

    Zhang, Q.; Tiefenbacher, K.

    2015-03-01

    In nature, complex terpene natural products are formed by the so-called tail-to-head terpene (THT) cyclization. The cationic reaction cascade is promoted efficiently in complex enzyme pockets, in which cationic intermediates and transition states are stabilized. In solution, the reaction is hard to control and man-made catalysts able to perform selective THT cyclizations are lacking. We herein report the first example of a successful THT cyclization inside a supramolecular structure. The basic mode of operation in cyclase enzymes was mimicked successfully and a catalytic non-stop THT was achieved with geranyl acetate as the substrate. The results presented have implications for the postulated reaction mechanism in cyclase enzymes. Evidence indicates that the direct isomerization of a geranyl cation to the cisoid isomer, which so far was considered unlikely, is feasible.

  6. Stereochemical diversity in asymmetric cyclization via memory of chirality.

    PubMed

    Kawabata, Takeo; Matsuda, Seiji; Kawakami, Shimpei; Monguchi, Daiki; Moriyama, Katsuhiko

    2006-12-01

    An enantiodivergent asymmetric cyclization of N-Boc-N-omega-bromoalkyl-alpha-amino acid derivatives has been developed. With potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lithium amide bases in THF. Chirality of the parent amino acids was preserved during enolate formation and cyclization to give aza-cyclic amino acids in up to 98% ee with retention of configuration or inversion of configuration, depending on the reaction conditions. Thus, both enantiomers of cyclic amino acids with a tetrasubstituted stereocenter were prepared in high enantiomeric purity from readily available l-alpha-amino acids. This protocol is also applicable to a spirocyclization and an intramolecular conjugate addition of alpha-amino acid derivatives, giving either of the enantiomers of a diazaspiro compound and a tetrahydroisoquinoline derivative, respectively, in up to 99% ee.

  7. The role of structural parameters in DNA cyclization

    DOE PAGES

    Alexandrov, Ludmil B.; Bishop, Alan R.; Rasmussen, Kim O.; Alexandrov, Boian S.

    2016-02-04

    The intrinsic bendability of DNA plays an important role with relevance for myriad of essential cellular mechanisms. The flexibility of a DNA fragment can be experimentally and computationally examined by its propensity for cyclization, quantified by the Jacobson-Stockmayer J factor. In this paper, we use a well-established coarse-grained three-dimensional model of DNA and seven distinct sets of experimentally and computationally derived conformational parameters of the double helix to evaluate the role of structural parameters in calculating DNA cyclization.

  8. WDM backbone network with guaranteed performance planning

    NASA Astrophysics Data System (ADS)

    Liang, Peng; Sheng, Wang; Zhong, Xusi; Li, Lemin

    2005-11-01

    Wavelength-Division multiplexing (WDM), which allows a single fibre to carry multiple signals simultaneously, has been widely used to increase link capacity and is a promising technology in backbone transport network. But designing such WDM backbone network is hard for two reasons, one is the uncertainty of future traffic demand, the other is difficulty of planning of the backup resource for failure conditions. As a result, enormous amount of link capacity for the network has to be provided for the network. Recently, a new approach called Valiant Load-Balanced Scheme (VLBS) has been proposed to design the WDM backbone network. The network planned by Valiant Load-Balanced Scheme is insensitive to the traffic and continues to guarantee performance under a user defined number of link or node failures. In this paper, the Valiant Load-Balanced Scheme (VLBS) for backbone network planning has been studied and a new Valiant Load-Balanced Scheme has been proposed. Compared with the early work, the new Valiant Load-Balanced Scheme is much more general and can be used for the computation of the link capacity of both homogeneous and heterogeneous networks. The abbreviation for the general Valiant Load-Balanced Scheme is GVLBS. After a brief description of the VLBS, we will give the detail derivation of the GVLBS. The central concept of the derivation of GVLBS is transforming the heterogeneous network into a homogeneous network, and taking advantage of VLBS to get GVLBS. Such transformation process is described and the derivation and analysis of GVLBS for link capacity under normal and failure conditions is also given. The numerical results show that GVLBS can compute the minimum link capacity required for the heterogeneous backbone network under different conditions (normal or failure).

  9. Cyclic Graft Copolymer Unimolecular Micelles: Effects of Cyclization on Particle Morphology and Thermoresponsive Behavior

    PubMed Central

    2016-01-01

    The synthesis of cyclic amphiphilic graft copolymers with a hydrophobic polycarbonate backbone and hydrophilic poly(N-acryloylmorpholine) (PNAM) side arms via a combination of ring-opening polymerization (ROP), cyclization via copper-catalyzed azide–alkyne cycloaddition (CuAAC), and reversible addition–fragmentation chain transfer (RAFT) polymerization is reported. The ability of these cyclic graft copolymers to form unimolecular micelles in water is explored using a combination of light scattering, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryoTEM) analyses, where particle size was found to increase with increasing PNAM arm length. Further analysis revealed differences in the solution conformations, loading capabilities, and morphologies of the cyclic graft copolymers in comparison to equivalent linear graft copolymer unimolecular micelle analogues. Furthermore, the cyclic and linear graft copolymers were found to exhibit significantly different cloud point temperatures. This study highlights how subtle changes in polymer architecture (linear graft copolymer versus cyclic graft copolymer) can dramatically influence a polymer’s nanostructure and its properties. PMID:27175037

  10. Catalytic Control in Cyclizations: From Computational Mechanistic Understanding to Selectivity Prediction.

    PubMed

    Peng, Qian; Paton, Robert S

    2016-05-17

    catalyst structures for enantioselective cycloisomerizations. Calculations have revealed that stepwise C-C bond formation and proton transfer dictate the exclusive endo diastereoselectivity of the intramolecular Michael addition to form 2-azabicyclo[3.3.1]nonane skeletons catalyzed by primary amines. These insights have led to development of a highly enantioselective catalyst with higher atom economy than previous generations. This Account also explores transition-metal-catalyzed cycloisomerizations, where our theoretical investigations have uncovered an unexpected reaction pathway in the [5 + 2] cycloisomerization of ynamides. This has led to the design of new phosphoramidite ligands to enable double-stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings. Computational understanding of the factors responsible for the regio-, enantio-, and diasterocontrol is shown to generate tangible predictions leading to an acceleration of catalyst development for selective cyclizations. PMID:27137131

  11. Catalytic asymmetric Torgov cyclization: a concise total synthesis of (+)-estrone.

    PubMed

    Prévost, Sébastien; Dupré, Nathalie; Leutzsch, Markus; Wang, Qinggang; Wakchaure, Vijay; List, Benjamin

    2014-08-11

    An asymmetric Torgov cyclization, catalyzed by a novel, highly Brønsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. This method was applied in a very short synthesis of (+)-estrone.

  12. Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst

    PubMed Central

    2015-01-01

    A heterogeneous gold catalyst with remarkable activity for promoting the electrophilic reactions of aryl vinyl ketones and aryl dienyl ketones is described. The catalyst is easy to prepare, is robust, and can be recycled. Low loadings are effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts. PMID:24432741

  13. Palladium(II) Catalyzed Cyclization-Carbonylation-Cyclization Coupling Reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides Using Molecular Oxygen as the Terminal Oxidant.

    PubMed

    Shen, Rong; Kusakabe, Taichi; Yatsu, Tomofumi; Kanno, Yuichiro; Takahashi, Keisuke; Nemoto, Kiyomitsu; Kato, Keisuke

    2016-01-01

    An efficient Pd(II)/Pd⁰-p-benzoquinone/hydroquinone-CuCl₂/CuCl catalyst system was developed that uses environmentally friendly molecular oxygen as the terminal oxidant to catalyze the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynyl phenyl) (methoxymethyl) sulfides. PMID:27607997

  14. A cyclization-carbonylation-cyclization coupling reaction of (ortho-alkynyl phenyl) (methoxymethyl) sulfides with the palladium(II)-bisoxazoline catalyst.

    PubMed

    Jiang, Yiyun; Kusakabe, Taichi; Takahashi, Keisuke; Kato, Keisuke

    2014-06-01

    A cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynylphenyl) (methoxymethyl) sulfides, catalyzed by (box)Pd(II) complexes, afforded symmetrical ketones bearing two benzo[b]thiophene groups in good to excellent yields. This method is applicable to a broad range of substrates.

  15. Palladium(II) Catalyzed Cyclization-Carbonylation-Cyclization Coupling Reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides Using Molecular Oxygen as the Terminal Oxidant.

    PubMed

    Shen, Rong; Kusakabe, Taichi; Yatsu, Tomofumi; Kanno, Yuichiro; Takahashi, Keisuke; Nemoto, Kiyomitsu; Kato, Keisuke

    2016-09-05

    An efficient Pd(II)/Pd⁰-p-benzoquinone/hydroquinone-CuCl₂/CuCl catalyst system was developed that uses environmentally friendly molecular oxygen as the terminal oxidant to catalyze the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynyl phenyl) (methoxymethyl) sulfides.

  16. Telephone wire is backbone of security system

    SciTech Connect

    Brede, K.; Rackson, L.T.

    1995-09-01

    Video provides a variety of low-cost, high-quality solutions in today`s security environment. Cost-conscious managers of power generation stations, casinos, prison facilities, military bases and office buildings are considering using regular telephone wire (unshielded twisted pair-UTP) within their existing systems as the backbone of a video to the PC, personal and video-conferencing and training are other areas where phone wire in a building can save money and provide an alternative to coax or fiber for video. More and more, businesses and government agencies are meeting their needs efficiently by using telephone wires for more than just telephones.

  17. Cyclization of peptoids by formation of boronate esters

    PubMed Central

    Chirayil, Sara; Luebke, Kevin J.

    2011-01-01

    Introduction of conformational constraints into peptoids (N-substituted oligoglycines) will enable new applications in molecular recognition and self-assembly. Peptoids that contain both a phenylboronic acid side chain and a vicinal diol cyclize by intramolecular condensation to form boronate esters. A fluorescent indicator of free boronic acid was used to assay esterification. A galactose moiety 2 to 5 monomer units away from a boronic acid side chain in a peptoid reacts with the boronic acid in competition with the indicator. The intramolecular reaction predominates in each case, with 80–90% of the peptoid cyclized. When the diol is a simple 2,3-dihydroxypropyl group, esterification is less favored but still appreciable. PMID:22611292

  18. Functionalization, cyclization and antiviral activity of A-secotriterpenoids.

    PubMed

    Grishko, Victoria V; Galaiko, Natalia V; Tolmacheva, Irina A; Kucherov, Igor I; Eremin, Vladimir F; Boreko, Eugene I; Savinova, Olga V; Slepukhin, Pavel A

    2014-08-18

    Triterpene derivatives with an α,β-alkenenitrile moiety in the five-membered ring A have been synthesized by nitrile anion cyclizations of 1-cyano-2,3-secotriterpenoids. Oxime-containing precursors, 2,3-secointermediates and five-membered ring A products of cyclizations were screened for in vitro antiviral activity against enveloped viruses - influenza A virus and human immunodeficiency virus type I (HIV-1). Lupane ketoxime and the 2,3-secolupane C-3 aldoxime which possess antiviral activities against both influenza A virus (EC50 12.9-18.2 μM) and HIV-1 (EC50 0.06 μM) were the most promising compounds. PMID:24997292

  19. The first examples of Nazarov cyclizations leading to annulated pyrroles.

    PubMed

    Song, Chuanjun; Knight, David W; Whatton, Maria A

    2006-01-01

    [reaction: see text] Reactions between alpha-substituted unsaturated carboxylic acids 20 and N-tosylpyrroles [14, 23] in the presence of trifluoroacetic anhydride result in smooth alpha-acylation of the pyrrole, followed by Nazarov cyclization to give 50-80% yields of cyclopenta[b]pyrroles. The presence of an alpha-substituent in the unsaturated acid appears to be mandatory. PMID:16381593

  20. Enabling New Modes of Reactivity via Constrictive Binding in a Supramolecular-Assembly-Catalyzed Aza-Prins Cyclization.

    PubMed

    Kaphan, David M; Toste, F Dean; Bergman, Robert G; Raymond, Kenneth N

    2015-07-29

    Supramolecular assembly 1 catalyzes a bimolecular aza-Prins cyclization featuring an unexpected transannular 1,5-hydride transfer. This reaction pathway, which is promoted by constrictive binding within the supramolecular cavity of 1, is kinetically disfavored in the absence of 1, as evidenced by the orthogonal reactivity observed in bulk solution. Mechanistic investigation through kinetic analysis and isotopic labeling studies indicates that the rate-limiting step of the transformation is the encapsulation of a transient iminium ion and supports the proposed 1,5-hydride transfer mechanism. This represents a rare example of such an extreme divergence of product selectivity observed within a catalytic metal-ligand supramolecular enzyme mimic.

  1. Nonlinear backbone torsional pair correlations in proteins

    PubMed Central

    Long, Shiyang; Tian, Pu

    2016-01-01

    Protein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions, and occur on widely different and relatively longer time scales. In contrast, correlations between backbone torsions in stable α helices and β strands are mainly linear and spatially short-ranged, and are more likely to associate with harmonic local torsional motion. Further analysis revealed that the direct cause of nonlinear contributions are heterogeneous linear correlations. These findings implicate a general search strategy for novel allosteric modulation sites of protein activities. PMID:27708342

  2. Nonlinear backbone torsional pair correlations in proteins

    NASA Astrophysics Data System (ADS)

    Long, Shiyang; Tian, Pu

    2016-10-01

    Protein allostery requires dynamical structural correlations. Physical origin of which, however, remain elusive despite intensive studies during last two and half decades. Based on analysis of molecular dynamics (MD) simulation trajectories for ten proteins with different sizes and folds, we found that nonlinear backbone torsional pair (BTP) correlations, which are mainly spatially long-ranged and are dominantly executed by loop residues, exist extensively in most analyzed proteins. Examination of torsional motion for correlated BTPs suggested that such nonlinear correlations are mainly associated aharmonic torsional state transitions and in some cases strongly anisotropic local torsional motion of participating torsions, and occur on widely different and relatively longer time scales. In contrast, correlations between backbone torsions in stable α helices and β strands are mainly linear and spatially short-ranged, and are more likely to associate with harmonic local torsional motion. Further analysis revealed that the direct cause of nonlinear contributions are heterogeneous linear correlations. These findings implicate a general search strategy for novel allosteric modulation sites of protein activities.

  3. Tissue-specific expression of head-to-tail cyclized miniproteins in Violaceae and structure determination of the root cyclotide Viola hederacea root cyclotide1.

    PubMed

    Trabi, Manuela; Craik, David J

    2004-08-01

    The plant cyclotides are a family of 28 to 37 amino acid miniproteins characterized by their head-to-tail cyclized peptide backbone and six absolutely conserved Cys residues arranged in a cystine knot motif: two disulfide bonds and the connecting backbone segments form a loop that is penetrated by the third disulfide bond. This knotted disulfide arrangement, together with the cyclic peptide backbone, renders the cyclotides extremely stable against enzymatic digest as well as thermal degradation, making them interesting targets for both pharmaceutical and agrochemical applications. We have examined the expression patterns of these fascinating peptides in various Viola species (Violaceae). All tissue types examined contained complex mixtures of cyclotides, with individual profiles differing significantly. We provide evidence for at least 57 novel cyclotides present in a single Viola species (Viola hederacea). Furthermore, we have isolated one cyclotide expressed only in underground parts of V. hederacea and characterized its primary and three-dimensional structure. We propose that cyclotides constitute a new family of plant defense peptides, which might constitute an even larger and, in their biological function, more diverse family than the well-known plant defensins.

  4. Synthesis of 2-azaindolizines by using an iodine-mediated oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides and an investigation of their photophysical properties.

    PubMed

    Shibahara, Fumitoshi; Kitagawa, Asumi; Yamaguchi, Eiji; Murai, Toshiaki

    2006-11-23

    Iodine-mediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides serves as an efficient and versatile method for the preparation of 2-azaindolizines (imidazo[1,5-a]pyridines) and rare 2-azaindolizine sulfur-bridged dimers. The 2-azaindolizines prepared in this manner are readily converted to a variety of fluorescent compounds by using transition-metal-catalyzed cross-coupling reactions. [reaction: see text]. PMID:17107087

  5. Copper-Mediated [3 + 2] Oxidative Cyclization Reaction of N-Tosylhydrazones and β-Ketoesters: Synthesis of 2,3,5-Trisubstituted Furans.

    PubMed

    Huang, Yubing; Li, Xianwei; Yu, Yue; Zhu, Chuanle; Wu, Wanqing; Jiang, Huanfeng

    2016-06-17

    The first attempt at utilizing N-tosylhydrazones as two-carbon synthons has been successfully achieved, which underwent a copper-mediated [3 + 2] oxidative cyclization reaction to afford 2,3,5-trisubstituted furans in moderate to good yields. The features of this method include inexpensive metal catalyst, readily available substrates, high regioselectivity, and convenient operation. The studies provide important approaches for further exploration of the powerful and diverse reaction abilities of N-tosylhydrazones. PMID:27227374

  6. Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators.

    PubMed

    Bandyopadhyay, Anupam; Gao, Jianmin

    2016-02-24

    As a rich source of therapeutic agents, peptide natural products usually adopt a cyclic or multicyclic scaffold that minimizes structural flexibility to favor target binding. Inspired by nature, chemists have been interested in developing synthetic cyclic and multicyclic peptides that serve as biological probes and potential therapeutics. Herein we describe a novel strategy for peptide cyclization in which intramolecular iminoboronate formation allows spontaneous cyclization under physiologic conditions to yield monocyclic and bicyclic peptides. Importantly the iminoboronate-based cyclization can be rapidly reversed in response to multiple stimuli, including pH, oxidation, and small molecules. This highly versatile strategy for peptide cyclization should find applications in many areas of chemical biology.

  7. Sofosbuvir as backbone of interferon free treatments.

    PubMed

    Bourlière, Marc; Oules, Valèrie; Ansaldi, Christelle; Adhoute, Xavier; Castellani, Paul

    2014-12-15

    Sofosbuvir is the first-in-class NS5B nucleotide analogues to be launched for hepatitis C virus (HCV) treatment. Its viral potency, pangenotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Recent data demonstrated that sofosbuvir either with ribavirin alone or in combination with other direct-acting antivirals (DAAs) as daclatasvir, ledipasvir or simeprevir are able to cure HCV in at least 90% or over of patients. Treatment experienced genotype 3 population may remain the most difficult to treat population, but ongoing DAA combination studies will help to fill this gap. Safety profile of sofosbuvir or combination with other DAAs is good. Resistance to sofosbuvir did not appear as a significant issue. The rationale for using this class of drug and the available clinical data are reviewed.

  8. Extracting the information backbone in online system.

    PubMed

    Zhang, Qian-Ming; Zeng, An; Shang, Ming-Sheng

    2013-01-01

    Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity) of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such "less can be more" feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency.

  9. Metal-binding and redox properties of substituted linear and cyclic ATCUN motifs.

    PubMed

    Neupane, Kosh P; Aldous, Amanda R; Kritzer, Joshua A

    2014-10-01

    The amino-terminal copper and nickel binding (ATCUN) motif is a short peptide sequence found in human serum albumin and other proteins. Synthetic ATCUN-metal complexes have been used to oxidatively cleave proteins and DNA, cross-link proteins, and damage cancer cells. The ATCUN motif consists of a tripeptide that coordinates Cu(II) and Ni(II) ions in a square planar geometry, anchored by chelation sites at the N-terminal amine, histidine imidazole and two backbone amides. Many studies have shown that the histidine is required for tight binding and square planar geometry. Previously, we showed that macrocyclization of the ATCUN motif can lead to high-affinity binding with altered metal ion selectivity and enhanced Cu(II)/Cu(III) redox cycling (Inorg. Chem. 2013, 52, 2729-2735). In this work, we synthesize and characterize several linear and cyclic ATCUN variants to explore how substitutions at the histidine alter the metal-binding and catalytic properties. UV-visible spectroscopy, EPR spectroscopy and mass spectrometry indicate that cyclization can promote the formation of ATCUN-like complexes even in the absence of imidazole. We also report several novel ATCUN-like complexes and quantify their redox properties. These findings further demonstrate the effects of conformational constraints on short, metal-binding peptides, and also provide novel redox-active metallopeptides suitable for testing as catalysts for stereoselective or regioselective oxidation reactions.

  10. Metal-Binding and Redox Properties of Substituted Linear and Cyclic ATCUN Motifs

    PubMed Central

    Neupane, Kosh P.; Aldous, Amanda R.; Kritzer, Joshua A.

    2014-01-01

    The amino-terminal copper and nickel binding (ATCUN) motif is a short peptide sequence found in human serum albumin and other proteins. Synthetic ATCUN-metal complexes have been used to oxidatively cleave proteins and DNA, cross-link proteins, and damage cancer cells. The ATCUN motif consists of a tripeptide that coordinates Cu(II) and Ni(II) ions in a square planar geometry, anchored by chelation sites at the N-terminal amine, histidine imidazole and two backbone amides. Many studies have shown that the histidine is required for tight binding and square planar geometry. Previously, we showed that macrocyclization of the ATCUN motif can lead to high-affinity binding with altered metal ion selectivity and enhanced Cu(II)/Cu(III) redox cycling (Inorg. Chem. 2013, 52, 2729-2735). In this work, we synthesize and characterize several linear and cyclic ATCUN variants to explore how substitutions at the histidine alter the metal-binding and catalytic properties. UV-visible spectroscopy, EPR spectroscopy and mass spectrometry indicate that cyclization can promote the formation of ATCUN-like complexes even in the absence of imidazole. We also report several novel ATCUN-like complexes and quantify their redox properties. These findings further demonstrate the effects of conformational constraints on short, metal-binding peptides, and also provide novel redox-active metallopeptides suitable for testing as catalysts for stereoselective or regioselective oxidation reactions. PMID:24980953

  11. Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with αα Domain Architecture That Catalyzes a Unique Cyclization-Fragmentation Reaction Sequence.

    PubMed

    Harris, Golda G; Lombardi, Patrick M; Pemberton, Travis A; Matsui, Tsutomu; Weiss, Thomas M; Cole, Kathryn E; Köksal, Mustafa; Murphy, Frank V; Vedula, L Sangeetha; Chou, Wayne K W; Cane, David E; Christianson, David W

    2015-12-01

    Geosmin synthase from Streptomyces coelicolor (ScGS) catalyzes an unusual, metal-dependent terpenoid cyclization and fragmentation reaction sequence. Two distinct active sites are required for catalysis: the N-terminal domain catalyzes the ionization and cyclization of farnesyl diphosphate to form germacradienol and inorganic pyrophosphate (PPi), and the C-terminal domain catalyzes the protonation, cyclization, and fragmentation of germacradienol to form geosmin and acetone through a retro-Prins reaction. A unique αα domain architecture is predicted for ScGS based on amino acid sequence: each domain contains the metal-binding motifs typical of a class I terpenoid cyclase, and each domain requires Mg(2+) for catalysis. Here, we report the X-ray crystal structure of the unliganded N-terminal domain of ScGS and the structure of its complex with three Mg(2+) ions and alendronate. These structures highlight conformational changes required for active site closure and catalysis. Although neither full-length ScGS nor constructs of the C-terminal domain could be crystallized, homology models of the C-terminal domain were constructed on the basis of ∼36% sequence identity with the N-terminal domain. Small-angle X-ray scattering experiments yield low-resolution molecular envelopes into which the N-terminal domain crystal structure and the C-terminal domain homology model were fit, suggesting possible αα domain architectures as frameworks for bifunctional catalysis.

  12. Enantioselective Synthesis of 4- and 6-Azaindolines by a Cation-Directed Cyclization

    PubMed Central

    2016-01-01

    Functionalized 4- and 6-azaindolines are accessible with high levels of enantioselectivity by the cation-directed cyclization of aminopyridine-derived imines via phase-transfer catalysis. The extension of this methodology to diastereoselective cyclizations is also described. PMID:27709963

  13. Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives accelerated by microwave irradiation.

    PubMed

    Bachu, Prabhakar; Akiyama, Takahiko

    2009-07-15

    The Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives was developed. Microwave irradiation accelerated the Nazarov cyclization significantly at 40 degrees C to give cyclopenta[b]pyrrole derivatives in excellent yields with high trans selectivity. PMID:19447615

  14. NHC Backbone Configuration in Ruthenium-Catalyzed Olefin Metathesis.

    PubMed

    Paradiso, Veronica; Costabile, Chiara; Grisi, Fabia

    2016-01-20

    The catalytic properties of olefin metathesis ruthenium complexes bearing N-heterocyclic carbene ligands with stereogenic centers on the backbone are described. Differences in catalytic behavior depending on the backbone configurations of symmetrical and unsymmetrical NHCs are discussed. In addition, an overview on asymmetric olefin metathesis promoted by chiral catalysts bearing C₂-symmetric and C₁-symmetric NHCs is provided.

  15. NHC Backbone Configuration in Ruthenium-Catalyzed Olefin Metathesis.

    PubMed

    Paradiso, Veronica; Costabile, Chiara; Grisi, Fabia

    2016-01-01

    The catalytic properties of olefin metathesis ruthenium complexes bearing N-heterocyclic carbene ligands with stereogenic centers on the backbone are described. Differences in catalytic behavior depending on the backbone configurations of symmetrical and unsymmetrical NHCs are discussed. In addition, an overview on asymmetric olefin metathesis promoted by chiral catalysts bearing C₂-symmetric and C₁-symmetric NHCs is provided. PMID:26805793

  16. Which one is preferred: Myers-Saito cyclization of ene-yne-allene or Garratt-Braverman cyclization of conjugated bisallenic sulfone? A theoretical and experimental study.

    PubMed

    Basak, Amit; Das, Sanket; Mallick, Dibyendu; Jemmis, Eluvathingal D

    2009-11-01

    A competitive scenario between Myers-Saito (MS) and Garratt-Braverman (GB) cyclization has been created in a molecule. High-level computations indicate a preference for GB over MS cyclization. The activation energies for the rate-determining steps of the GB and MS cyclizations were found to be the same (24.4 kcal/mol) at the B3LYP/6-31G* level of theory; thus, from the kinetic point of view, both reactions are feasible. However, the main biradical intermediate GB2 of the GB reaction is 6.2 kcal/mol lower in energy than the biradical MS2, which is the main intermediate of MS reaction, so GB cyclization is thermodynamically favored over MS cyclization. To verify the prediction by computational techniques, bisenediynyl sulfones 1-4 and bisenediynyl sulfoxide 17 were synthesized. Under basic conditions, these molecules isomerized to a system possessing both the ene-yne-allene and the bisallenic sulfone. The isolation of only one product, identified as the corresponding naphthalene- or benzene-fused sulfone 8-11, indicated the occurrence of GB cyclization as the sole reaction pathway. No product corresponding to the MS cyclization pathway could be isolated. Though the theoretical prediction showed a preference for the GB pathway over the MS pathway, the exclusive preference for GB over MS cyclization is very striking. Further analysis showed that the intramolecular self-quenching nature of the GB pathway may play an important role in the complete preference for this reaction. Apart from the mechanistic studies, these sulfones showed DNA cleavage activity that had an inverse relation with the reactivity order. Our findings are important for the design of artificial DNA-cleaving agents.

  17. Highly enantioselective reductive cyclization of acetylenic aldehydes via rhodium catalyzed asymmetric hydrogenation.

    PubMed

    Rhee, Jong Uk; Krische, Michael J

    2006-08-23

    Catalytic hydrogenation of acetylenic aldehydes 1a-12a using chirally modified cationic rhodium catalysts enables highly enantioselective reductive cyclization to afford cyclic allylic alcohols 1b-12b. Using an achiral hydrogenation catalyst, the chiral racemic acetylenic aldehydes 13a-15a engage in highly syn-diastereoselective reductive cyclizations to afford cyclic allylic alcohols 13b-15b. Ozonolysis of cyclization products 7b and 9b allows access to optically enriched alpha-hydroxy ketones 7c and 9c. Reductive cyclization of enyne 7a under a deuterium atmosphere provides the monodeuterated product deuterio-7b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle. These hydrogen-mediated transformations represent the first examples of the enantioselective reductive cyclization of acetylenic aldehydes. PMID:16910650

  18. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting...

  19. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting...

  20. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting...

  1. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting...

  2. 40 CFR 721.990 - 1,4-Benzedicarboxylic acid, dimethyl ester, polymer with 1,4 - butanediol, cyclized.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ester, polymer with 1,4 - butanediol, cyclized. 721.990 Section 721.990 Protection of Environment..., dimethyl ester, polymer with 1,4 - butanediol, cyclized. (a) Chemical substance and significant new uses..., polymer with 1,4 - butanediol, cyclized (PMN P-00-0789; CAS No. 263244-54-8) is subject to reporting...

  3. Free backbone carbonyls mediate rhodopsin activation.

    PubMed

    Kimata, Naoki; Pope, Andreyah; Sanchez-Reyes, Omar B; Eilers, Markus; Opefi, Chikwado A; Ziliox, Martine; Reeves, Philip J; Smith, Steven O

    2016-08-01

    Conserved prolines in the transmembrane helices of G-protein-coupled receptors (GPCRs) are often considered to function as hinges that divide the helix into two segments capable of independent motion. Depending on their potential to hydrogen-bond, the free C=O groups associated with these prolines can facilitate conformational flexibility, conformational switching or stabilization of the receptor structure. To address the role of conserved prolines in family A GPCRs through solid-state NMR spectroscopy, we focus on bovine rhodopsin, a GPCR in the visual receptor subfamily. The free backbone C=O groups on helices H5 and H7 stabilize the inactive rhodopsin structure through hydrogen-bonds to residues on adjacent helices. In response to light-induced isomerization of the retinal chromophore, hydrogen-bonding interactions involving these C=O groups are released, thus facilitating repacking of H5 and H7 onto the transmembrane core of the receptor. These results provide insights into the multiple structural and functional roles of prolines in membrane proteins. PMID:27376589

  4. Extracting the Information Backbone in Online System

    PubMed Central

    Zhang, Qian-Ming; Zeng, An; Shang, Ming-Sheng

    2013-01-01

    Information overload is a serious problem in modern society and many solutions such as recommender system have been proposed to filter out irrelevant information. In the literature, researchers have been mainly dedicated to improving the recommendation performance (accuracy and diversity) of the algorithms while they have overlooked the influence of topology of the online user-object bipartite networks. In this paper, we find that some information provided by the bipartite networks is not only redundant but also misleading. With such “less can be more” feature, we design some algorithms to improve the recommendation performance by eliminating some links from the original networks. Moreover, we propose a hybrid method combining the time-aware and topology-aware link removal algorithms to extract the backbone which contains the essential information for the recommender systems. From the practical point of view, our method can improve the performance and reduce the computational time of the recommendation system, thus improving both of their effectiveness and efficiency. PMID:23690946

  5. A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

    PubMed Central

    Mousseau, James J.; Morten, Christopher J.

    2013-01-01

    Ladder polyether natural products are a class of natural products denoted by their high functional group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogues with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases they provide near complete endo to exo selectivity in the cyclization of epoxy alcohols, thereby strongly favouring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template. PMID:23775936

  6. Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

    PubMed Central

    McCulloch, Kathryn M.; McCranie, Emilianne K.; Smith, Jarrod A.; Sarwar, Maruf; Mathieu, Jeannette L.; Gitschlag, Bryan L.; Du, Yu; Bachmann, Brian O.; Iverson, T. M.

    2015-01-01

    Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate–dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics. PMID:26240321

  7. An optimized intein-mediated protein ligation approach for the efficient cyclization of cysteine-rich proteins.

    PubMed

    Tarasava, Katsiaryna; Freisinger, Eva

    2014-12-01

    Head-to-tail backbone cyclization of proteins is a widely used approach for the improvement of protein stability. One way to obtain cyclic proteins via recombinant expression makes use of engineered Intein tags, which are self-cleaving protein domains. In this approach, pH-induced self-cleavage of the N-terminal Intein tag generates an N-terminal cysteine residue at the target protein, which then attacks in an intramolecular reaction the C-terminal thioester formed by the second C-terminal Intein tag resulting in the release of the cyclic target protein. In the current work we aimed to produce a cyclic analog of the small γ-Ec-1 domain of the wheat metallothionein, which contains six cysteine residues. During the purification process we faced several challenges, among them premature cleavage of one or the other Intein tag resulting in decreasing yields and contamination with linear species. To improve efficiency of the system we applied a number of optimizations such as the introduction of a Tobacco etch virus cleavage site and an additional poly-histidine tag. Our efforts resulted in the production of a cyclic protein in moderate yields without any contamination with linear protein species.

  8. The myosin filament XIV backbone structure.

    PubMed Central

    Ashton, F T; Weisel, J; Pepe, F A

    1992-01-01

    The substructure of the thick filaments of chemically skinned chicken pectoralis muscle was investigated by electron microscopy. Images of transverse sections of the myosin filaments were determined to have threefold symmetry by cross-correlation analysis, which gives an unbiased determination of the rotational symmetry of the images. Resolution, using the phase residual test (Frank et al. 1981. Science [Wash. DC]. 214:1353-1355), was found to be between 3.2 and 3.6 nm. Three arrangements of nine subfilaments in the backbone were found in all regions of the filament at ionic strengths of 20 and 200 mM. In the average images of two of these, there were three dense central subfilaments and three pairs of subfilaments on the surface of the thick filament. In the average image of the third arrangement, all of the protein mass of the nine subfilaments was on the surface of the filament with three of them showing less variation in position than the others. A fourth arrangement appearing to be transitional between two of these was seen often at 200 mM ionic strength and only rarely at 20 mM. On average, the myosin subfilaments were parallel to the long axis of the filament. The different arrangements of subfilaments appear to be randomly distributed among the filaments in a transverse section of the A-band. Relative rotational orientations with respect to the hexagonal filament lattice, using the three densest subfilaments as reference showed a major clustering (32%) of filaments within one 10 degrees spread, a lesser clustering (15%) at 90 degrees to the first, and the remainder scattered thinly over the rest of the 120 degrees range. There was no obvious pattern of distribution of the two predominant orientations that could define a superlattice in the filament lattice. Images FIGURE 2 FIGURE 6 FIGURE 8 PMID:1617136

  9. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    SciTech Connect

    Wilmarth, J. E.; Sturrock, J. C.; Gallegos, F. R.

    1998-12-10

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  10. Radiation safety system (RSS) backbones: Design, engineering, fabrication and installation

    SciTech Connect

    Wilmarth, J.E.; Sturrock, J.C.; Gallegos, F.R.

    1998-12-01

    The Radiation Safety System (RSS) Backbones are part of an electrical/electronic/mechanical system insuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS Backbones control the safety fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low energy beam transport. The Backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the Backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two Linac Backbone segments and experimental area segments form a continuous cable plant over 3,500 feet from beam plugs to the tip on the longest tail. The Backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  11. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    SciTech Connect

    Wilmarth, J.E.; Sturrock, J.C.; Gallegos, F.R.

    1998-12-01

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely. {copyright} {ital 1998 American Institute of Physics.}

  12. Radiation Safety System (RSS) backbones: Design, engineering, fabrication, and installation

    NASA Astrophysics Data System (ADS)

    Wilmarth, J. E.; Sturrock, J. C.; Gallegos, F. R.

    1998-12-01

    The Radiation Safety System (RSS) backbones are part of an electrical/electronic/mechanical system ensuring safe access and exclusion of personnel to areas at the Los Alamos Neutron Science Center (LANSCE) accelerator. The RSS backbones control the safety-fusible beam plugs which terminate transmission of accelerated ion beams in response to predefined conditions. Any beam or access fault of the backbone inputs will cause insertion of the beam plugs in the low-energy beam transport. The backbones serve the function of tying the beam plugs to the access control systems, beam spill monitoring systems and current-level limiting systems. In some ways the backbones may be thought of as a spinal column with beam plugs at the head and nerve centers along the spinal column. The two linac backbone segments and the experimental area segments form a continuous cable plant over 3500 feet from the beam plugs to the tip on the longest tail. The backbones were installed in compliance with current safety standards, such as installation of the two segments in separate conduits or tray. Monitoring for ground-faults and input wiring verification was an added enhancement to the system. The system has the capability to be tested remotely.

  13. Inter- versus intra-molecular cyclization of tripeptides containing tetrahydrofuran amino acids: a density functional theory study on kinetic control.

    PubMed

    Kumar, N V Suresh; Priyakumar, U Deva; Singh, Harjinder; Roy, Saumya; Chakraborty, Tushar Kanti

    2012-07-01

    Density functional B3LYP method was used to investigate the preference of intra- and inter-molecular cyclizations of linear tripeptides containing tetrahydrofuran amino acids. Two distinct model pathways were conceived for the cyclization reaction, and all possible transition states and intermediates were located. Analysis of the energetics indicate intermolecular cyclization being favored by both thermodynamic and kinetic control. Geometric and NBO analyses were performed to explain the trends obtained along both the reaction pathways. Conceptual density functional theory-based reactive indices also show that reaction pathways leading to intermolecular cyclization of the tripeptides are relatively more facile compared to intramolecular cyclization.

  14. Engineering Short Preorganized Peptide Sequences for Metal Ion Coordination: Copper(II) a Case Study.

    PubMed

    Lima, L M P; Iranzo, O

    2016-01-01

    Peptides are multidentate chiral ligands capable of coordinating different metal ions. Nowadays, they can be obtained with high yield and purity, thanks to the advances on peptide/protein chemistry as well as in equipment (peptide synthesizers). Based on the identity and length of their amino acid sequences, peptides can present different degrees of flexibility and folding. Although short peptide sequences (<20 amino acids) usually lack structure in solution, different levels of structural preorganization can be induced by introducing conformational constraints, such as β-turn/loop template sequences and backbone cyclization. For all these reasons, and the fact that one is not restricted to use proteinogenic amino acids, small peptidic scaffolds constitute a simple and versatile platform for the development of inorganic systems with tailor-made properties and functions. Here we outline a general approach to the design of short preorganized peptide sequences (10-16 amino acids) for metal ion coordination. Based on our experience, we present a general scheme for the design, synthesis, and characterization of these peptidic scaffolds and provide protocols for the study of their metal ion coordination properties. PMID:27586340

  15. Engineering Short Preorganized Peptide Sequences for Metal Ion Coordination: Copper(II) a Case Study.

    PubMed

    Lima, L M P; Iranzo, O

    2016-01-01

    Peptides are multidentate chiral ligands capable of coordinating different metal ions. Nowadays, they can be obtained with high yield and purity, thanks to the advances on peptide/protein chemistry as well as in equipment (peptide synthesizers). Based on the identity and length of their amino acid sequences, peptides can present different degrees of flexibility and folding. Although short peptide sequences (<20 amino acids) usually lack structure in solution, different levels of structural preorganization can be induced by introducing conformational constraints, such as β-turn/loop template sequences and backbone cyclization. For all these reasons, and the fact that one is not restricted to use proteinogenic amino acids, small peptidic scaffolds constitute a simple and versatile platform for the development of inorganic systems with tailor-made properties and functions. Here we outline a general approach to the design of short preorganized peptide sequences (10-16 amino acids) for metal ion coordination. Based on our experience, we present a general scheme for the design, synthesis, and characterization of these peptidic scaffolds and provide protocols for the study of their metal ion coordination properties.

  16. Sortase A as a tool for high-yield histatin cyclization.

    PubMed

    Bolscher, Jan G M; Oudhoff, Menno J; Nazmi, Kamran; Antos, John M; Guimaraes, Carla P; Spooner, Eric; Haney, Evan F; Garcia Vallejo, Juan J; Vogel, Hans J; van't Hof, Wim; Ploegh, Hidde L; Veerman, Enno C I

    2011-08-01

    Cyclic peptides are highly valued tools in biomedical research. In many cases, they show higher receptor affinity, enhanced biological activity, and improved serum stability. Technical difficulties in producing cyclic peptides, especially larger ones, in appreciable yields have precluded a prolific use in biomedical research. Here, we describe a novel and efficient cyclization method that uses the peptidyl-transferase activity of the Staphylococcus aureus enzyme sortase A to cyclize linear synthetic precursor peptides. As a model, we used histatin 1, a 38-mer salivary peptide with motogenic activity. Chemical cyclization of histatin 1 resulted in ≤ 3% yields, whereas sortase-mediated cyclization provided a yield of >90%. The sortase-cyclized peptide displayed a maximum wound closure activity at 10 nM, whereas the linear peptide displayed maximal activity at 10 μM. Circular dichroism and NMR spectroscopic analysis of the linear and cyclic peptide in solution showed no evidence for conformational changes, suggesting that structural differences due to cyclization only became manifest when these peptides were located in the binding domain of the receptor. The sortase-based cyclization technology provides a general method for easy and efficient manufacturing of large cyclic peptides.

  17. Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates

    PubMed Central

    Spencer, William T.; Vaidya, Tulaza; Frontier, Alison J.

    2013-01-01

    The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in the study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediate central to the cyclization. Methods reviewed include carbon-heteroatom ionization, functionalization of a double bond, nucleophilic addition, or electrocyclic ring opening. Additional variations employ unconventional substrates to produce novel pentacycles, such as the iso- and imino-Nazarov. Herein, we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization. PMID:24348092

  18. A sampling approach for protein backbone fragment conformations.

    PubMed

    Yu, J Y; Zhang, W

    2013-01-01

    In protein structure prediction, backbone fragment bias information can narrow down the conformational space of the whole polypeptide chain significantly. Unlike existing methods that use fragments as building blocks, the paper presents a probabilistic sampling approach for protein backbone torsion angles by modelling angular correlation of (phi, psi) with a directional statistics distribution. Given a protein sequence and secondary structure information, this method samples backbone fragments conformations by using a backtrack sampling algorithm for the hidden Markov model with multiple inputs and a single output. The proposed approach is applied to a fragment library, and some well-known structural motifs are sampled very well on the optimal path. Computational results show that the method can help to obtain native-like backbone fragments conformations. PMID:23777175

  19. A backbone lever-arm effect enhances polymer mechanochemistry.

    PubMed

    Klukovich, Hope M; Kouznetsova, Tatiana B; Kean, Zachary S; Lenhardt, Jeremy M; Craig, Stephen L

    2013-02-01

    Mechanical forces along a polymer backbone can be used to bring about remarkable reactivity in embedded mechanically active functional groups, but little attention has been paid to how a given polymer backbone delivers that force to the reactant. Here, single-molecule force spectroscopy was used to directly quantify and compare the forces associated with the ring opening of gem-dibromo and gem-dichlorocyclopropanes affixed along the backbone of cis-polynorbornene and cis-polybutadiene. The critical force for isomerization drops by about one-third in the polynorbornene scaffold relative to polybutadiene. The root of the effect lies in more efficient chemomechanical coupling through the polynorbornene backbone, which acts as a phenomenological lever with greater mechanical advantage than polybutadiene. The experimental results are supported computationally and provide the foundation for a new strategy by which to engineer mechanochemical reactivity. PMID:23344431

  20. A backbone lever-arm effect enhances polymer mechanochemistry

    NASA Astrophysics Data System (ADS)

    Klukovich, Hope M.; Kouznetsova, Tatiana B.; Kean, Zachary S.; Lenhardt, Jeremy M.; Craig, Stephen L.

    2013-02-01

    Mechanical forces along a polymer backbone can be used to bring about remarkable reactivity in embedded mechanically active functional groups, but little attention has been paid to how a given polymer backbone delivers that force to the reactant. Here, single-molecule force spectroscopy was used to directly quantify and compare the forces associated with the ring opening of gem-dibromo and gem-dichlorocyclopropanes affixed along the backbone of cis-polynorbornene and cis-polybutadiene. The critical force for isomerization drops by about one-third in the polynorbornene scaffold relative to polybutadiene. The root of the effect lies in more efficient chemomechanical coupling through the polynorbornene backbone, which acts as a phenomenological lever with greater mechanical advantage than polybutadiene. The experimental results are supported computationally and provide the foundation for a new strategy by which to engineer mechanochemical reactivity.

  1. Photocleavage of the Polypeptide Backbone by 2-Nitrophenylalanine

    PubMed Central

    Peters, Francis B.; Brock, Ansgar; Wang, Jiangyun; Schultz, Peter G.

    2009-01-01

    Summary Photocleavage of the polypeptide backbone is potentially a powerful and general method to activate or deactivate functional peptides and proteins with high spatial and temporal resolution. Here we show that 2-nitrophenylalanine is able to photochemically cleave the polypeptide backbone by an unusual cinnoline forming reaction. This unnatural amino acid was genetically encoded in E. coli, and protein containing 2-nitrophenylalanine was expressed and site specifically photocleaved. PMID:19246005

  2. Triazine-Based Sequence-Defined Polymers with Side-Chain Diversity and Backbone-Backbone Interaction Motifs.

    PubMed

    Grate, Jay W; Mo, Kai-For; Daily, Michael D

    2016-03-14

    Sequence control in polymers, well-known in nature, encodes structure and functionality. Here we introduce a new architecture, based on the nucleophilic aromatic substitution chemistry of cyanuric chloride, that creates a new class of sequence-defined polymers dubbed TZPs. Proof of concept is demonstrated with two synthesized hexamers, having neutral and ionizable side chains. Molecular dynamics simulations show backbone-backbone interactions, including H-bonding motifs and pi-pi interactions. This architecture is arguably biomimetic while differing from sequence-defined polymers having peptide bonds. The synthetic methodology supports the structural diversity of side chains known in peptides, as well as backbone-backbone hydrogen-bonding motifs, and will thus enable new macromolecules and materials with useful functions. PMID:26865312

  3. Radical-driven peptide backbone dissociation tandem mass spectrometry.

    PubMed

    Oh, Han Bin; Moon, Bongjin

    2015-01-01

    In recent years, a number of novel tandem mass spectrometry approaches utilizing radical-driven peptide gas-phase fragmentation chemistry have been developed. These approaches show a peptide fragmentation pattern quite different from that of collision-induced dissociation (CID). The peptide fragmentation features of these approaches share some in common with electron capture dissociation (ECD) or electron transfer dissociation (ETD) without the use of sophisticated equipment such as a Fourier-transform mass spectrometer. For example, Siu and coworkers showed that CID of transition metal (ligand)-peptide ternary complexes led to the formation of peptide radical ions through dissociative electron transfer (Chu et al., 2000. J Phys Chem B 104:3393-3397). The subsequent collisional activation of the generated radical ions resulted in a number of characteristic product ions, including a, c, x, z-type fragments and notable side-chain losses. Another example is the free radical initiated peptide sequencing (FRIPS) approach, in which Porter et al. and Beauchamp et al. independently introduced a free radical initiator to the primary amine group of the lysine side chain or N-terminus of peptides (Masterson et al., 2004. J Am Chem Soc 126:720-721; Hodyss et al., 2005 J Am Chem Soc 127: 12436-12437). Photodetachment of gaseous multiply charged peptide anions (Joly et al., 2008. J Am Chem Soc 130:13832-13833) and UV photodissociation of photolabile radical precursors including a C-I bond (Ly & Julian, 2008. J Am Chem Soc 130:351-358; Ly & Julian, 2009. J Am Soc Mass Spectrom 20:1148-1158) also provide another route to generate radical ions. In this review, we provide a brief summary of recent results obtained through the radical-driven peptide backbone dissociation tandem mass spectrometry approach.

  4. Iminoboronate-Based Peptide Cyclization That Responds to pH, Oxidation, and Small Molecule Modulators.

    PubMed

    Bandyopadhyay, Anupam; Gao, Jianmin

    2016-02-24

    As a rich source of therapeutic agents, peptide natural products usually adopt a cyclic or multicyclic scaffold that minimizes structural flexibility to favor target binding. Inspired by nature, chemists have been interested in developing synthetic cyclic and multicyclic peptides that serve as biological probes and potential therapeutics. Herein we describe a novel strategy for peptide cyclization in which intramolecular iminoboronate formation allows spontaneous cyclization under physiologic conditions to yield monocyclic and bicyclic peptides. Importantly the iminoboronate-based cyclization can be rapidly reversed in response to multiple stimuli, including pH, oxidation, and small molecules. This highly versatile strategy for peptide cyclization should find applications in many areas of chemical biology. PMID:26859098

  5. Enantioselective cyclization of enamide-ynes and application to the synthesis of the kopsifoline core

    PubMed Central

    Corkey, Britton K.; Heller, Stephen T.; Wang, Yi-Ming

    2013-01-01

    We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline alkaloids. PMID:23772095

  6. Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

    PubMed Central

    Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J.

    2013-01-01

    A study of the reactivity and diastereoselectivity of the Lewis acid-promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone, followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic ynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID:23724905

  7. Total Synthesis of (±)–Rocaglamide via Oxidation-Initiated Nazarov Cyclization

    PubMed Central

    Malona, John A.; Cariou, Kevin; Spencer, William T.

    2012-01-01

    This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)–rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide. PMID:22283818

  8. SpyTag/SpyCatcher Cyclization Enhances the Thermostability of Firefly Luciferase

    PubMed Central

    Si, Meng; Xu, Qing

    2016-01-01

    SpyTag can spontaneously form a covalent isopeptide bond with its protein partner SpyCatcher. Firefly luciferase from Photinus pyralis was cyclized in vivo by fusing SpyCatcher at the N terminus and SpyTag at the C terminus. Circular LUC was more thermostable and alkali-tolerant than the wild type, without compromising the specific activity. Structural analysis indicated that the cyclized LUC increased the thermodynamic stability of the structure and remained more properly folded at high temperatures when compared with the wild type. We also prepared an N-terminally and C-terminally shortened form of the SpyCatcher protein and cyclization using this truncated form led to even more thermostability than the original form. Our findings suggest that cyclization with SpyTag and SpyCatcher is a promising and effective strategy to enhance thermostability of enzymes. PMID:27658030

  9. Organic Photocatalytic Cyclization of Polyenes: A Visible-Light-Mediated Radical Cascade Approach.

    PubMed

    Yang, Zhongbo; Li, Han; Zhang, Long; Zhang, Ming-Tian; Cheng, Jin-Pei; Luo, Sanzhong

    2015-10-12

    A visible-light-mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosin Y as photocatalyst in hexafluoro-2-propanol. The catalyst system is also suitable for 1,3-dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols.

  10. Peptide Amphiphile Nanofibers with Conjugated Polydiacetylene Backbones in Their Core

    PubMed Central

    Hsu, Lorraine; Cvetanovich, Gregory L.; Stupp, Samuel I.

    2008-01-01

    The coupling of electronic and biological functionality through self-assembly is an interesting target in supramolecular chemistry. We report here on a set of diacetylene-derivatized peptide amphiphiles (PAs) that react to form conjugated polydiacetylene backbones following self-assembly into cylindrical nanofibers. The polymerization reaction yields highly conjugated backbones when the peptidic segment of the PAs has a linear, as opposed to a branched, architecture. Given the topotactic nature of the polymerization, these results suggest that a high degree of internal order exists in the supramolecular nanofibers formed by the linear PA. On the basis of microscopy, the formation of a polydiacetylene backbone to covalently connect the β-sheets that help form the fibers does not disrupt the fiber shape. Interestingly, we observe the appearance of a polydiacetylene (PDA) circular dichroism band at 547 nm in linear PA nanofibers suggesting the conjugated backbone in the core of the nanostructures is twisted. We believe this CD signal is due to chiral induction by the β-sheets, which are normally twisted in helical fashion. Heating and cooling shows simultaneous changes in β-sheet and conjugated backbone structure, indicating they are both correlated. At the same time, poor polymerization in nanofibers formed by branched PAs indicates that less internal order exists in these nanostructures and, as expected, then a circular dichroism signal is not observed for the conjugated backbone. The general variety of materials investigated here has the obvious potential to couple electronic properties and in vitro bioactivity. Furthermore, the polymerization of monomers in peptide amphiphile assemblies by a rigid conjugated backbone also leads to mechanical robustness and insolubility, two properties that may be important for the patterning of these materials at the cellular scale. PMID:18314978

  11. SpyTag/SpyCatcher cyclization confers resilience to boiling on a mesophilic enzyme.

    PubMed

    Schoene, Christopher; Fierer, Jacob O; Bennett, S Paul; Howarth, Mark

    2014-06-10

    SpyTag is a peptide that spontaneously forms an amide bond with its protein partner SpyCatcher. SpyTag was fused at the N terminus of β-lactamase and SpyCatcher at the C terminus so that the partners could react to lock together the termini of the enzyme. The wild-type enzyme aggregates above 37 °C, with irreversible loss of activity. Cyclized β-lactamase was soluble even after heating at 100 °C; after cooling, the catalytic activity was restored. SpyTag/SpyCatcher cyclization led to a much larger increase in stability than that achieved through point mutation or alternative approaches to cyclization. Cyclized dihydrofolate reductase was similarly resilient. Analyzing unfolding through calorimetry indicated that cyclization did not increase the unfolding temperature but rather facilitated refolding after thermal stress. SpyTag/SpyCatcher sandwiching represents a simple and efficient route to enzyme cyclization, with potential to greatly enhance the robustness of biocatalysts.

  12. Silver(I)-Mediated Phosphorylation/Cyclization Cascade of N-Cyanamide Alkenes for Divergent Access to Quinazolinones and Dihydroisoquinolinones.

    PubMed

    Zheng, Jing; Zhang, Yan; Wang, Dahai; Cui, Sunliang

    2016-04-15

    A silver(I)-mediated phosphorylation/cyclization radical cascade of N-cyanamide alkenes has been developed. The addition of in situ generated phosphorus radical to N-cyanamide alkenes triggers the cascade, resulting in late-stage cyclization toward divergent access to 4-quinazolinones and dihydroisoquinolinones. Both terminal and internal N-cyanamide alkenes are applicable in this protocol, and the cyclizations are consistent with Baldwin's rule.

  13. Solvent-Dependent Pyranopterin Cyclization in Molybdenum Cofactor Model Complexes.

    PubMed

    Williams, Benjamin R; Gisewhite, Douglas; Kalinsky, Anna; Esmail, Alisha; Burgmayer, Sharon J Nieter

    2015-09-01

    The conserved pterin dithiolene ligand that coordinates molybdenum (Mo) in the cofactor (Moco) of mononuclear Mo enzymes can exist in both a tricyclic pyranopterin dithiolene form and as a bicyclic pterin-dithiolene form as observed in protein crystal structures of several bacterial molybdoenzymes. Interconversion between the tricyclic and bicyclic forms via pyran scission and cyclization has been hypothesized to play a role in the catalytic mechanism of Moco. Therefore, understanding the interconversion between the tricyclic and bicyclic forms, a type of ring-chain tautomerism, is an important aspect of study to understand its role in catalysis. In this study, equilibrium constants (K(eq)) as well as enthalpy, entropy, and free energy values are obtained for pyran ring tautomerism exhibited by two Moco model complexes, namely, (Et4N)[Tp*Mo(O)(S2BMOPP)] (1) and (Et4N)[Tp*Mo(O)(S2PEOPP)] (2), as a solvent-dependent equilibrium process. Keq values obtained from (1)H NMR data in seven deuterated solvents show a correlation between solvent polarity and tautomer form, where solvents with higher polarity parameters favor the pyran form.

  14. Gold-Catalyzed Cyclization Processes: Pivotal Avenues for Organic Synthesis.

    PubMed

    Kumar, Amit; Singh, Sukhdev; Sharma, Sunil K; Parmar, Virinder S; Van der Eycken, Erik V

    2016-02-01

    Over the years, gold catalysis has materialized as an incredible synthetic approach among the scientific community. Due to the trivial reaction conditions and great functional compatibility, these progressions are synthetically expedient, because practitioners can implement them to build intricate architectures from readily amassed building blocks with high bond forming indices. The incendiary growth of gold catalysts in organic synthesis has been demonstrated as one of the most prevailing soft Lewis acids for electrophilic activation of carbon-carbon multiple bonds towards a great assortment of nucleophiles. Nowadays, organic chemists consistently employ gold catalysts to carry out a diverse array of organic transformations to build unprecedented molecular architectures. Despite all these achievements and a plethora of reports, many vital challenges remain. In this account, we describe the reactivity of various gold catalysts towards cyclization processes developed over the years. These protocols give access to a wide scope of polyheterocyclic structures, containing different medium-sized ring skeletons. This is interesting, as the quest for highly selective reactions to assemble diversely functionalized products has attracted much attention. We envisage that these newly developed chemo-, regio-, and diastereoselective protocols could provide an expedient route to architecturally cumbersome heterocycles of importance for the pharmaceutical industry.

  15. Structural dependencies of protein backbone 2JNC' couplings.

    PubMed

    Juranić, Nenad; Dannenberg, J J; Cornilescu, Gabriel; Salvador, Pedro; Atanasova, Elena; Ahn, Hee-Chul; Macura, Slobodan; Markley, John L; Prendergast, Franklyn G

    2008-04-01

    Protein folding can introduce strain in peptide covalent geometry, including deviations from planarity that are difficult to detect, especially for a protein in solution. We have found dependencies in protein backbone (2)J(NC') couplings on the planarity and the relative orientation of the sequential peptide planes. These dependences were observed in experimental (2)J(NC') couplings from seven proteins, and also were supported by DFT calculations for a model tripeptide. Findings indicate that elevated (2)J(NC') couplings may serve as reporters of structural strain in the protein backbone imposed by protein folds. Such information, supplemented with the H-bond strengths derived from (h3)J(NC') couplings, provides useful insight into the overall energy profile of the protein backbone in solution.

  16. Adding Diverse Noncanonical Backbones to Rosetta: Enabling Peptidomimetic Design

    PubMed Central

    Craven, Timothy W.; Butterfoss, Glenn L.; Chou, Fang-Chieh; Lyskov, Sergey; Bullock, Brooke N.; Watkins, Andrew; Labonte, Jason W.; Pacella, Michael; Kilambi, Krishna Praneeth; Leaver-Fay, Andrew; Kuhlman, Brian; Gray, Jeffrey J.; Bradley, Philip; Kirshenbaum, Kent; Arora, Paramjit S.; Das, Rhiju; Bonneau, Richard

    2013-01-01

    Peptidomimetics are classes of molecules that mimic structural and functional attributes of polypeptides. Peptidomimetic oligomers can frequently be synthesized using efficient solid phase synthesis procedures similar to peptide synthesis. Conformationally ordered peptidomimetic oligomers are finding broad applications for molecular recognition and for inhibiting protein-protein interactions. One critical limitation is the limited set of design tools for identifying oligomer sequences that can adopt desired conformations. Here, we present expansions to the ROSETTA platform that enable structure prediction and design of five non-peptidic oligomer scaffolds (noncanonical backbones), oligooxopiperazines, oligo-peptoids, -peptides, hydrogen bond surrogate helices and oligosaccharides. This work is complementary to prior additions to model noncanonical protein side chains in ROSETTA. The main purpose of our manuscript is to give a detailed description to current and future developers of how each of these noncanonical backbones was implemented. Furthermore, we provide a general outline for implementation of new backbone types not discussed here. To illustrate the utility of this approach, we describe the first tests of the ROSETTA molecular mechanics energy function in the context of oligooxopiperazines, using quantum mechanical calculations as comparison points, scanning through backbone and side chain torsion angles for a model peptidomimetic. Finally, as an example of a novel design application, we describe the automated design of an oligooxopiperazine that inhibits the p53-MDM2 protein-protein interaction. For the general biological and bioengineering community, several noncanonical backbones have been incorporated into web applications that allow users to freely and rapidly test the presented protocols (http://rosie.rosettacommons.org). This work helps address the peptidomimetic community's need for an automated and expandable modeling tool for noncanonical

  17. Structure of Epi-Isozizaene Synthase from Streptomyces coelicolor A3(2), a Platform for New Terpenoid Cyclization Templates

    SciTech Connect

    Aaron, Julie A.; Lin, Xin; Cane, David E.; Christianson, David W.

    2010-06-21

    The X-ray crystal structure of recombinant epi-isozizaene synthase (EIZS), a sesquiterpene cyclase from Streptomyces coelicolor A3(2), has been determined at 1.60 {angstrom} resolution. Specifically, the structure of wild-type EIZS is that of its closed conformation in complex with three Mg{sup 2+} ions, inorganic pyrophosphate (PP{sub i}), and the benzyltriethylammonium cation (BTAC). Additionally, the structure of D99N EIZS has been determined in an open, ligand-free conformation at 1.90 {angstrom} resolution. Comparison of these two structures provides the first view of conformational changes required for substrate binding and catalysis in a bacterial terpenoid cyclase. Moreover, the binding interactions of BTAC may mimic those of a carbocation intermediate in catalysis. Accordingly, the aromatic rings of F95, F96, and F198 appear to be well-oriented to stabilize carbocation intermediates in the cyclization cascade through cation-{pi} interactions. Mutagenesis of aromatic residues in the enzyme active site results in the production of alternative sesquiterpene product arrays due to altered modes of stabilization of carbocation intermediates as well as altered templates for the cyclization of farnesyl diphosphate. Accordingly, the 1.64 {angstrom} resolution crystal structure of F198A EIZS in a complex with three Mg{sup 2+} ions, PP{sub i}, and BTAC reveals an alternative binding orientation of BTAC; alternative binding orientations of a carbocation intermediate could lead to the formation of alternative products. Finally, the crystal structure of wild-type EIZS in a complex with four Hg{sup 2+} ions has been determined at 1.90 {angstrom} resolution, showing that metal binding triggers a significant conformational change of helix G to cap the active site.

  18. Cyclization strategies of meditopes: affinity and diffraction studies of meditope-Fab complexes.

    PubMed

    Bzymek, Krzysztof P; Ma, Yuelong; Avery, Kendra A; Horne, David A; Williams, John C

    2016-06-01

    Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented. The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic `pocket' and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope-Fab complex.

  19. Cyclization strategies of meditopes: affinity and diffraction studies of meditope–Fab complexes

    PubMed Central

    Bzymek, Krzysztof P.; Ma, Yuelong; Avery, Kendra A.; Horne, David A.; Williams, John C.

    2016-01-01

    Recently, a unique binding site for a cyclic 12-residue peptide was discovered within a cavity formed by the light and heavy chains of the cetuximab Fab domain. In order to better understand the interactions that drive this unique complex, a number of variants including the residues within the meditope peptide and the antibody, as well as the cyclization region of the meditope peptide, were created. Here, multiple crystal structures of meditope peptides incorporating different cyclization strategies bound to the central cavity of the cetuximab Fab domain are presented. The affinity of each cyclic derivative for the Fab was determined by surface plasmon resonance and correlated to structural differences. Overall, it was observed that the disulfide bond used to cyclize the peptide favorably packs against a hydrophobic ‘pocket’ and that amidation and acetylation of the original disulfide meditope increased the overall affinity ∼2.3-fold. Conversely, replacing the terminal cysteines with serines and thus creating a linear peptide reduced the affinity over 50-fold, with much of this difference being reflected in a decrease in the on-rate. Other cyclization methods, including the formation of a lactam, reduced the affinity but not to the extent of the linear peptide. Collectively, the structural and kinetic data presented here indicate that small perturbations introduced by different cyclization strategies can significantly affect the affinity of the meditope–Fab complex. PMID:27303895

  20. An Iodine‐Vapor‐Induced Cyclization in a Crystalline Molecular Flask

    PubMed Central

    Knichal, Jane V.; Shepherd, Helena J.; Wilson, Chick C.; Raithby, Paul R.

    2016-01-01

    Abstract A vapor‐induced cyclization has been observed in the host environment of a crystalline molecular flask (CMF), within which 1,8‐bis(2‐phenylethynyl)naphthalene (bpen), a diarenynyl system primed for cyclization, was exposed to iodine vapor to yield the corresponding indeno[2,1‐α]phenalene species. The cyclization process, unique in its vapor‐induced, solvent‐free nature, was followed spectroscopically, and found to occur concurrently with the displacement of lattice solvent for molecular iodine in CMF⋅0.75 bpen⋅2.25 CHCl3⋅H2O. The cyclization occurred under mild conditions and without the need to suspend the crystals in solvent. The ability of CMFs to host purely gas‐induced reactions is further highlighted by the subsequent sequential oxidation reaction of cyclized 7‐iodo‐12‐phenylindeno[2,1‐α]phenalene (ipp) with molecular oxygen derived from air, yielding 12‐hydroxy‐7‐iodo‐2‐phenylindeno[2,1‐α]phenalen‐1(12H)‐one (hipp). PMID:27060377

  1. Backbone Additivity in the Transfer Model of Protein Solvation

    SciTech Connect

    Hu, Char Y.; Kokubo, Hironori; Lynch, Gillian C.; Bolen, D Wayne; Pettitt, Bernard M.

    2010-05-01

    The transfer model implying additivity of the peptide backbone free energy of transfer is computationally tested. Molecular dynamics simulations are used to determine the extent of change in transfer free energy (ΔGtr) with increase in chain length of oligoglycine with capped end groups. Solvation free energies of oligoglycine models of varying lengths in pure water and in the osmolyte solutions, 2M urea and 2M trimethylamine N-oxide (TMAO), were calculated from simulations of all atom models, and ΔGtr values for peptide backbone transfer from water to the osmolyte solutions were determined. The results show that the transfer free energies change linearly with increasing chain length, demonstrating the principle of additivity, and provide values in reasonable agreement with experiment. The peptide backbone transfer free energy contributions arise from van der Waals interactions in the case of transfer to urea, but from electrostatics on transfer to TMAO solution. The simulations used here allow for the calculation of the solvation and transfer free energy of longer oligoglycine models to be evaluated than is currently possible through experiment. The peptide backbone unit computed transfer free energy of –54 cal/mol/Mcompares quite favorably with –43 cal/mol/M determined experimentally.

  2. Increasing protein production by directed vector backbone evolution

    PubMed Central

    2013-01-01

    Recombinant protein production in prokaryotic and eukaryotic organisms was a key enabling technology for the rapid development of industrial and molecular biotechnology. However, despite all progress the improvement of protein production is an ongoing challenge and of high importance for cost-effective enzyme production. With the epMEGAWHOP mutagenesis protocol for vector backbone optimization we report a novel directed evolution based approach to increase protein production levels by randomly introducing mutations in the vector backbone. In the current study we validate the epMEGAWHOP mutagenesis protocol for three different expression systems. The latter demonstrated the general applicability of the epMEGAWHOP method. Cellulase and lipase production was doubled in one round of directed evolution by random mutagenesis of pET28a(+) and pET22b(+) vector backbones. Protease production using the vector pHY300PLK was increased ~4-times with an average of ~1.25 mutations per kb vector backbone. The epMEGAWHOP does not require any rational understanding of the expression machinery and can generally be applied to enzymes, expression vectors and related hosts. epMEGAWHOP is therefore from our point of view a robust, rapid and straight forward alternative for increasing protein production in general and for biotechnological applications. PMID:23890095

  3. The Graphical Representation of the Digital Astronaut Physiology Backbone

    NASA Technical Reports Server (NTRS)

    Briers, Demarcus

    2010-01-01

    This report summarizes my internship project with the NASA Digital Astronaut Project to analyze the Digital Astronaut (DA) physiology backbone model. The Digital Astronaut Project (DAP) applies integrated physiology models to support space biomedical operations, and to assist NASA researchers in closing knowledge gaps related to human physiologic responses to space flight. The DA physiology backbone is a set of integrated physiological equations and functions that model the interacting systems of the human body. The current release of the model is HumMod (Human Model) version 1.5 and was developed over forty years at the University of Mississippi Medical Center (UMMC). The physiology equations and functions are scripted in an XML schema specifically designed for physiology modeling by Dr. Thomas G. Coleman at UMMC. Currently it is difficult to examine the physiology backbone without being knowledgeable of the XML schema. While investigating and documenting the tags and algorithms used in the XML schema, I proposed a standard methodology for a graphical representation. This standard methodology may be used to transcribe graphical representations from the DA physiology backbone. In turn, the graphical representations can allow examination of the physiological functions and equations without the need to be familiar with the computer programming languages or markup languages used by DA modeling software.

  4. Cooperative UAV-Based Communications Backbone for Sensor Networks

    SciTech Connect

    Roberts, R S

    2001-10-07

    The objective of this project is to investigate the use of unmanned air vehicles (UAVs) as mobile, adaptive communications backbones for ground-based sensor networks. In this type of network, the UAVs provide communication connectivity to sensors that cannot communicate with each other because of terrain, distance, or other geographical constraints. In these situations, UAVs provide a vertical communication path for the sensors, thereby mitigating geographic obstacles often imposed on networks. With the proper use of UAVs, connectivity to a widely disbursed sensor network in rugged terrain is readily achieved. Our investigation has focused on networks where multiple cooperating UAVs are used to form a network backbone. The advantage of using multiple UAVs to form the network backbone is parallelization of sensor connectivity. Many widely spaced or isolated sensors can be connected to the network at once using this approach. In these networks, the UAVs logically partition the sensor network into sub-networks (subnets), with one UAV assigned per subnet. Partitioning the network into subnets allows the UAVs to service sensors in parallel thereby decreasing the sensor-to-network connectivity. A UAV services sensors in its subnet by flying a route (path) through the subnet, uplinking data collected by the sensors, and forwarding the data to a ground station. An additional advantage of using multiple UAVs in the network is that they provide redundancy in the communications backbone, so that the failure of a single UAV does not necessarily imply the loss of the network.

  5. Protein-Backbone Thermodynamics across the Membrane Interface.

    PubMed

    Bereau, Tristan; Kremer, Kurt

    2016-07-01

    The thermodynamics of insertion of a protein in a membrane depends on the fine interplay between backbone and side-chain contributions interacting with the lipid environment. Using computer simulations, we probe how different descriptions of the backbone glycyl unit affect the thermodynamics of insertion of individual residues, dipeptides, and entire transmembrane helices. Due to the lack of reference data, we first introduce an efficient methodology to estimate atomistic potential of mean force (PMF) curves from a series of representative and uncorrelated coarse-grained (CG) snapshots. We find strong discrepancies between two CG models, Martini and PLUM, against reference atomistic PMFs and experiments. Atomistic simulations suggest a weak free energy of insertion between water and a POPC membrane for the glycyl unit, in overall agreement with experimental results despite severe assumptions in our calculations. We show that refining the backbone contribution in PLUM significantly improves the PMF of insertion of the WALP16 transmembrane peptide. An improper balance between the glycyl backbone and the attached side chain will lead to energetic artifacts, rationalizing Martini's overstabilization of WALP's adsorbed interfacial state. It illustrates difficulties associated with free-energy-based parametrizations of single-residue models, as the relevant free energy of partitioning used for force-field parametrization does not arise from the entire residue but rather the solvent-accessible chemical groups. PMID:27138459

  6. Total Synthesis of (+)-Sieboldine A: Evolution of A Pinacol-Terminated Cyclization Strategy

    PubMed Central

    Canham, Stephen M.; France, David J.; Overman, Larry E.

    2013-01-01

    This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study a number of pinacol-terminated cationic cyclizations were examined to form the cis-hydrindanone core of sieboldine A. Of these, a mild Au(I)-promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor. PMID:22734821

  7. Utility of Ligand Effect in Homogenous Gold Catalysis: Enabling Regiodivergent π-Bond-Activated Cyclization.

    PubMed

    Ding, Dong; Mou, Tao; Feng, Minghao; Jiang, Xuefeng

    2016-04-27

    Comprehensive utilization of both electronic and steric properties of ligands in homogeneous gold catalysis is achieved in the regiodivergent intramolecular hydroarylation of alkynes. A flexible electron-deficient phosphite ligand, combined with the readily transformable directing group methoxyl amide, is attached to a cationic Au(I) center in three-coordinate mode, affording sterically hindered ortho-position cyclization. Meanwhile, para-position cyclization is exclusively achieved with the assistance of a rigid electron-abundant phosphine ligand-based Au(I) catalyst, in which ligands manifest the compensating effect for cyclization through steric hindrance and electronic properties. By combining gold with silver catalysts, tetrahydropyrroloquinolinones possessing a congested tricyclic structure are obtained via a proven Au/Ag relay catalytic process. PMID:27058740

  8. Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space.

    PubMed

    Rolfe, Alan; Lushington, Gerald H; Hanson, Paul R

    2010-05-01

    The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic (DOS) strategy to probe chemical and biological space via a "Click, Click, Cyclize" protocol. In this DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and polar surface area (PSA) calculations.

  9. “Cation-Stitching Cascade”: exquisite control of terpene cyclization in cyclooctatin biosynthesis

    NASA Astrophysics Data System (ADS)

    Sato, Hajime; Teramoto, Kazuya; Masumoto, Yui; Tezuka, Noriyuki; Sakai, Kenta; Ueda, Shota; Totsuka, Yusuke; Shinada, Tetsuro; Nishiyama, Makoto; Wang, Chao; Kuzuyama, Tomohisa; Uchiyama, Masanobu

    2015-12-01

    Terpene cyclization is orchestrated by terpene cyclases, which are involved in the biosynthesis of various cyclic natural products, but understanding the origin and mechanism of the selectivity of terpene cyclization is challenging. In this work, we describe an in-depth mechanistic study on cyclooctatin biosynthesis by means of theoretical calculations combined with experimental methods. We show that the main framework of cyclooctatin is formed through domino-type carbocation transportation along the terpene chain, which we call a “cation-stitching cascade”, including multiple hydrogen-shifts and a ring rearrangement that elegantly determine the stereoselectivity.

  10. Tandem Electrocyclic Ring Opening/Radical Cyclization: Application to the Total Synthesis of Cribrostatin 6

    PubMed Central

    Knueppel, Daniel; Martin, Stephen F.

    2011-01-01

    A concise total synthesis ofcribrostatin 6 (1), an antimicrobial and antineoplastic agent,was accomplished using a tandem electrocyclic ring opening/radical cyclization sequence. Specifically, intermediate4 underwent a 4π-electrocyclic ring opening, radical cyclization, and homolytic aromatic substitution sequence followed by an oxidation to afford the natural product1in one pot. Owing to the rapid buildup of complexity in the key step, 1 could be synthesized from commercially available starting materials in only four linear steps. Application of this chemistry to the concise syntheses of analogs of cribrostatin 6 (1) is also reported. PMID:22125344

  11. Unciaphenol, an Oxygenated Analogue of the Bergman Cyclization Product of Uncialamycin Exhibits Anti-HIV Activity.

    PubMed

    Williams, David E; Bottriell, Helen; Davies, Julian; Tietjen, Ian; Brockman, Mark A; Andersen, Raymond J

    2015-11-01

    Unciaphenol (2), an oxygenated analogue of the Bergman cyclization product of the enediyne uncialamycin (1), has been isolated along with 1 from cultures of the actinomycete Streptomyces uncialis. It is proposed that the C-22 OH substituent in 2 might arise from the attack of a nucleophilic oxygen species on the p-benzyne diradical intermediate IA in the Bergman cyclization of 1. 2 shows in vitro anti-HIV activity against viral strains that are resistant to clinically utilized anti-retroviral therapies.

  12. “Cation-Stitching Cascade”: exquisite control of terpene cyclization in cyclooctatin biosynthesis

    PubMed Central

    Sato, Hajime; Teramoto, Kazuya; Masumoto, Yui; Tezuka, Noriyuki; Sakai, Kenta; Ueda, Shota; Totsuka, Yusuke; Shinada, Tetsuro; Nishiyama, Makoto; Wang, Chao; Kuzuyama, Tomohisa; Uchiyama, Masanobu

    2015-01-01

    Terpene cyclization is orchestrated by terpene cyclases, which are involved in the biosynthesis of various cyclic natural products, but understanding the origin and mechanism of the selectivity of terpene cyclization is challenging. In this work, we describe an in-depth mechanistic study on cyclooctatin biosynthesis by means of theoretical calculations combined with experimental methods. We show that the main framework of cyclooctatin is formed through domino-type carbocation transportation along the terpene chain, which we call a “cation-stitching cascade”, including multiple hydrogen-shifts and a ring rearrangement that elegantly determine the stereoselectivity. PMID:26681256

  13. Conversion of Substrate Analogs Suggests a Michael Cyclization in Iridoid Biosynthesis

    PubMed Central

    Lindner, Stephanie; Geu-Flores, Fernando; Bräse, Stefan; Sherden, Nathaniel H.; O’Connor, Sarah E.

    2014-01-01

    Summary The core structure of the iridoid monoterpenes is formed by a unique cyclization reaction. The enzyme that catalyzes this reaction, iridoid synthase, is mechanistically distinct from other terpene cyclases. Here we describe the synthesis of two substrate analogs to probe the mechanism of iridoid synthase. Enzymatic assay of these substrate analogs along with clues from the product profile of the native substrate strongly suggest that iridoid synthase utilizes a Michael reaction to achieve cyclization. This improved mechanistic understanding will facilitate the exploitation of the potential of iridoid synthase to synthesize new cyclic compounds from nonnatural substrates. PMID:25444551

  14. Observation of a thermally induced Bora-Nazarov cyclization at a phosphole framework.

    PubMed

    Möbus, Juri; Kehr, Gerald; Daniliuc, Constantin G; Mück-Lichtenfeld, Christian; Erker, Gerhard

    2015-10-12

    The reaction of the bis(enynyl)phosphanes 6 a,b with the electrophilic borane reagents RB(C6 F5 )2 (R=C6 F5 , CH2 CH2 Ph, CH3 ) gave phospholes cleanly in a 1,1-carboboration reaction sequence. Depending on the steric bulk, the resulting 2,5-alkenylphospholes underwent a thermally induced bora-Nazarov type cyclization. The equilibrium situation of these examples of a bora-Nazarov type cyclization was investigated in detail by NMR spectroscopy, X-ray crystal structure analysis, and DFT calculations. PMID:26094744

  15. Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins.

    PubMed

    Dornan, Peter K; Lee, Daniel; Grubbs, Robert H

    2016-05-25

    A tandem olefin metathesis/oxidative cyclization has been developed to synthesize 2,5-disubstituted tetrahydrofuran (THF) diols in a stereocontrolled fashion from simple olefin precursors. The ruthenium metathesis catalyst is converted into an oxidation catalyst in the second step and is thus responsible for both catalytic steps. The stereochemistry of the 1,5-diene intermediate can be controlled through the choice of catalyst and the type of metathesis conducted. This olefin stereochemistry then controls the THF diol stereochemistry through a highly stereospecific oxidative cyclization.

  16. Tandem Olefin Metathesis/Oxidative Cyclization: Synthesis of Tetrahydrofuran Diols from Simple Olefins.

    PubMed

    Dornan, Peter K; Lee, Daniel; Grubbs, Robert H

    2016-05-25

    A tandem olefin metathesis/oxidative cyclization has been developed to synthesize 2,5-disubstituted tetrahydrofuran (THF) diols in a stereocontrolled fashion from simple olefin precursors. The ruthenium metathesis catalyst is converted into an oxidation catalyst in the second step and is thus responsible for both catalytic steps. The stereochemistry of the 1,5-diene intermediate can be controlled through the choice of catalyst and the type of metathesis conducted. This olefin stereochemistry then controls the THF diol stereochemistry through a highly stereospecific oxidative cyclization. PMID:27133576

  17. Extracting the multiscale backbone of complex weighted networks

    PubMed Central

    Serrano, M. Ángeles; Boguñá, Marián; Vespignani, Alessandro

    2009-01-01

    A large number of complex systems find a natural abstraction in the form of weighted networks whose nodes represent the elements of the system and the weighted edges identify the presence of an interaction and its relative strength. In recent years, the study of an increasing number of large-scale networks has highlighted the statistical heterogeneity of their interaction pattern, with degree and weight distributions that vary over many orders of magnitude. These features, along with the large number of elements and links, make the extraction of the truly relevant connections forming the network's backbone a very challenging problem. More specifically, coarse-graining approaches and filtering techniques come into conflict with the multiscale nature of large-scale systems. Here, we define a filtering method that offers a practical procedure to extract the relevant connection backbone in complex multiscale networks, preserving the edges that represent statistically significant deviations with respect to a null model for the local assignment of weights to edges. An important aspect of the method is that it does not belittle small-scale interactions and operates at all scales defined by the weight distribution. We apply our method to real-world network instances and compare the obtained results with alternative backbone extraction techniques. PMID:19357301

  18. Determination of backbone nitrogen-nitrogen J correlations in proteins.

    PubMed

    Theis, K; Dingley, A J; Hoffmann, A; Omichinski, J G; Grzesiek, S

    1997-12-01

    Recently, a quantitative J correlation technique has been presented which makes use of homonuclear Hartmann-Hahn cross-polarization (TOCSY) to measure (3)J(C)'(C)' in proteins isotopically enriched with (13)C [Grzesiek, S. and Bax, A. (1997) J. Biomol. NMR, 9, 207-211]. Since homonuclear Hartmann-Hahn is twice as fast as conventional COSY transfer, this method is much less sensitive to transverse relaxation, which is the principal limiting factor in achieving long-range J-coupling correlations in macromolecules. Here we describe a similar experiment which is used to measure(3) J(NN) coupling constants between sequential amide(15) N nuclei in the backbone of ubiquitin. As expected from the low magnetic moment of (15)N, the (3)J(NN) coupling constants are exceedingly small, with values between 0.14 and 0.36 Hz for residues in β-conformations and values below 0.15 Hz for residues in α-conformations. In contrast to what is expected from a Karplus-type dependence on the backbone angle ψ, large differences in the values of(3) J(NN) are observed for a number of residues with very similar backbone ψ angles. A quantitative description of statistical and systematic errors, in particular of relaxation effects during the TOCSY transfer, shows that these differences are highly significant. PMID:20859784

  19. Catalytic Cyclization of o-Alkynyl Phenethylamines via Osmacyclopropene Intermediates: Direct Access to Dopaminergic 3-Benzazepines.

    PubMed

    Álvarez-Pérez, Andrea; González-Rodríguez, Carlos; García-Yebra, Cristina; Varela, Jesús A; Oñate, Enrique; Esteruelas, Miguel A; Saá, Carlos

    2015-11-01

    A novel osmium-catalyzed cyclization of o-alkynyl phenethylamines to give 3-benzazepines is reported. The procedure allows the straightforward preparation of a broad range of dopaminergic 3-benzazepine derivatives. Mechanistic investigations revealed that the process takes place via osmacyclopropene intermediates, which were isolated and characterized by X-ray crystallography.

  20. Solvent-free cyclization of linear dienes using olefin metathesis and the Thorpe-Ingold effect

    SciTech Connect

    Forbees, M.D.E.; Myers, T.L.; Maynard, H.D.; Schulz, G.R. ); Patton, J.T.; Smith, D.W. Jr.; Wagener, K.B. )

    1992-12-30

    The olefin metathesis reaction is of great synthetic utility in polymer chemistry. The recent development of ring-opening (ROMP) and acyclic diene (ADMET) metathesis polymerization reactions has opened new avenues for the synthesis of novel polymeric materials. Recently the authors used ADMET to synthesize several photochemically active poly(keto olefins) using the catalyst Mo(CHCMe[sub 2]Ph)(NAr)(OCMe(CF[sub 3])[sub 2])[sub 2] (Ar = 2,6-diisopropylphenyl) (1) developed by Schrock and co-workers in 1990. In the course of that work, they discovered that neat samples of highly substituted dienes will cyclize quantitatively via metathesis to give difunctional five- and seven-membered rings instead of the expected linear polymer. Examples of substituted diene cyclizations by metathesis even in the presence of a solvent are rare. Their systematic exploitation in organic synthesis has therefore been limited to two recent studies by Fu and Grubbs, who cyclized several substituted diene ethers, amines, and amides to unsaturated oxygen and nitrogen heterocycles. Cyclization of unsubstituted dienes in various solvents has been reported, but complete conversion occurred in only a few cases. Formation of cyclic alkene oligomers from back-biting during the ROMP reaction is also known. The reactions reported here are unusual in that they are intermolecular between catalyst and substrate, yet can give 100% yield of product solely from the monomer in the absence of solvent. 13 refs.

  1. Palladium-catalyzed synthesis of dibenzophosphole oxides via intramolecular dehydrogenative cyclization.

    PubMed

    Kuninobu, Yoichiro; Yoshida, Takuya; Takai, Kazuhiko

    2011-09-16

    Dibenzophosphole oxides were obtained from secondary hydrophosphine oxides with a biphenyl group by dehydrogenation via phosphine-hydrogen and carbon-hydrogen bond cleavage in the presence of a catalytic amount of palladium(II) acetate, Pd(OAc)(2). By using this reaction, a ladder-type dibenzophosphole oxide could also be synthesized by double intramolecular dehydrogenative cyclization. PMID:21819045

  2. Biomimetic cyclization of geraniol derivatives, a useful tool in the total synthesis of bioactive monocyclic terpenoids.

    PubMed

    Merlini, Valentina; Luparia, Marco; Porta, Alessio; Zanoni, Giuseppe; Vidari, Giovanni

    2011-04-01

    This review is a detailed account of authors' work in the field of biomimetic cyclization of geraniol-like dienes. The very high regio- and enantioselectivity achieved made these elegant reactions a viable tool for the synthesis of monocyclic building blocks used in the synthesis of valued terpenoids, like the precious aroma and perfume constituents' ionones and irones.

  3. Palladium(II)-Catalyzed Cyclization of Unsaturated Hydroperoxides for the Synthesis of 1,2-Dioxanes

    PubMed Central

    Harris, Jason R.; Waetzig, Shelli R.

    2009-01-01

    The cyclization of γ,δ-unsaturated tertiary hydroperoxides in the presence of a palladium(II) catalyst afforded 1,2-dioxanes resembling biologically active natural products. A variety of substrates were screened, and synthetic manipulations were accomplished to construct compounds with structural similarity to antimalarial targets. PMID:19555089

  4. Cyclization and crosslinking of polybutadiene in solution by electron beam irradiation

    SciTech Connect

    Hayashi, K.; Tachibana, M.; Okamura, S.

    1980-09-01

    Effects of electron beam irradiation on liquid polybutadiene in n-hexane solution were studied at -10/sup 0/C. With irradiation, crosslinking of the polymer and loss of double bond by cyclization took place at the same time. These reactions were retarded by the addition of DPPH or triethylamine which indicated that both radical and cationic mechanisms contributed to this system.

  5. Construction of a Spirooxindole Amide Library through Nitrile Hydrozirconation-Acylation-Cyclization Cascade

    PubMed Central

    LaPorte, Matthew G.; Tsegay, Sammi; Hong, Ki Bum; Lu, Chunliang; Fang, Cheng; Wang, Lirong; Xie, Xiang-Qun; Floreancig, Paul E.

    2013-01-01

    A library of spirooxindoles containing varied elements of structural and stereochemical diversity has been constructed via a three step, one pot nitrile hydrozirconation-acylation-cyclization reaction sequence from common acyclic indole intermediates. The resulting library was evaluated for novelty through comparison with MLSMR and Maybridge compound collections. PMID:23731121

  6. Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions.

    PubMed

    Holan, Martin; Pohl, Radek; Císařová, Ivana; Klepetářová, Blanka; Jones, Peter G; Jahn, Ullrich

    2015-06-26

    Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with α-benzylidene and α-alkylidene β-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C-C bonds and one C-O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.

  7. Cyclization of Fungal Nonribosomal Peptides by a Terminal Condensation-Like Domain

    PubMed Central

    Gao, Xue; Haynes, Stuart W.; Ames, Brian D.; Wang, Peng; Vien, Linda P.; Walsh, Christopher T.; Tang, Yi

    2012-01-01

    Cyclization of linear peptidyl precursors produced by nonribosomal peptide synthetases (NRPSs) is an important step in the biosynthesis of bioactive cyclic peptides. Whereas bacterial NRPSs use thioesterase (TE) domains to perform the cyclization, fungal NRPSs have apparently evolved to use a different enzymatic route. In verified fungal NRPSs that produce macrocyclic peptides, each megasynthetase terminates with a condensation-like (CT) domain that may perform the macrocyclization reaction. To probe the role of such a CT domain, we reconstituted the activities of the Penicillium aethiopicum trimodular NPRS TqaA in Saccharomyces cerevisiae and in vitro. Together with a reconstituted bimodular NRPS AnaPS, we dissected the cyclization steps of TqaA in transforming the linear anthranilate-D-tryptophan-L-alanyl tripeptide into fumiquinazoline F. Extensive biochemical and mutational studies confirmed the essential role of the CT domain in catalyzing cyclization in a thiolation domain-dependent fashion. Our work provided evidence of a likely universal macrocyclization strategy employed by fungal NRPSs. PMID:22902615

  8. Cyclization of fungal nonribosomal peptides by a terminal condensation-like domain.

    PubMed

    Gao, Xue; Haynes, Stuart W; Ames, Brian D; Wang, Peng; Vien, Linda P; Walsh, Christopher T; Tang, Yi

    2012-10-01

    Cyclization of linear peptidyl precursors produced by nonribosomal peptide synthetases (NRPSs) is an important step in the biosynthesis of bioactive cyclic peptides. Whereas bacterial NRPSs use thioesterase domains to perform the cyclization, fungal NRPSs have apparently evolved to use a different enzymatic route. In verified fungal NRPSs that produce macrocyclic peptides, each megasynthetase terminates with a condensation-like (C(T)) domain that may perform the macrocyclization reaction. To probe the role of such a C(T) domain, we reconstituted the activities of the Penicillium aethiopicum trimodular NPRS TqaA in Saccharomyces cerevisiae and in vitro. Together with the reconstituted bimodular NRPS AnaPS, we dissected the cyclization steps of TqaA in transforming the linear anthranilate-D-tryptophan-L-alanyl tripeptide into fumiquinazoline F. Extensive biochemical and mutational studies confirmed the essential role of the C(T) domain in catalyzing cyclization in a thiolation domain-dependent fashion. Our work provides evidence of a likely universal macrocyclization strategy used by fungal NRPSs. PMID:22902615

  9. meso-Phbox-Pd(II) catalyzed tandem carbonylative cyclization of 1-ethynyl-1-propargyl acetate.

    PubMed

    Kato, Keisuke; Teraguchi, Ryuhei; Motodate, Satoshi; Uchida, Akira; Mochida, Tomoyuki; Peganova, Tat'yana A; Vologdin, Nikolai V; Akita, Hiroyuki

    2008-08-21

    Palladium(II) catalyzed carbonylation of 1-ethynyl-1-propargyl acetate is described; in the absence of the bisoxazoline (box) ligand, the second triple bond did not react, affording cyclic orthoesters and . The use of meso-Phbox-Pd(ii) strikingly changed the course of the reaction, yielding bicyclic lactone by tandem carbonylative cyclization as a result of insertion of the second triple bond.

  10. Nazarov cyclization of dienylaziridines: synthesis of cyclopentadienyl/hydrinedienyl/indenyl glycines.

    PubMed

    Sudhakar, Gangarajula; Reddy, Karla Janardhan; Nanubolu, Jagadesh Babu

    2015-09-01

    Cyclopentadienyl, hydrinedienyl, and indenyl glycines were synthesized using dienylaziridines as Nazarov cyclization precursors for the first time. Several substrates were synthesized to demonstrate the compatibility of this reaction. Asymmetric synthesis of these amino acids was also developed to show the additional scope of this method. PMID:26203635

  11. Enantioselective Total Synthesis of (−)-Nardoaristolone B via a Gold(I)-Catalyzed Oxidative Cyclization

    PubMed Central

    2015-01-01

    The first enantioselective total synthesis of (−)-nardoaristolone B is accomplished by the implementation of an enantio- and diastereoselective copper(I)-catalyzed conjugate addition/enolate trapping sequence and a gold(I)-catalyzed oxidative cyclization (intermolecular oxidant), employed for the first time in total synthesis. PMID:25563976

  12. Catalytic Cyclization of o-Alkynyl Phenethylamines via Osmacyclopropene Intermediates: Direct Access to Dopaminergic 3-Benzazepines.

    PubMed

    Álvarez-Pérez, Andrea; González-Rodríguez, Carlos; García-Yebra, Cristina; Varela, Jesús A; Oñate, Enrique; Esteruelas, Miguel A; Saá, Carlos

    2015-11-01

    A novel osmium-catalyzed cyclization of o-alkynyl phenethylamines to give 3-benzazepines is reported. The procedure allows the straightforward preparation of a broad range of dopaminergic 3-benzazepine derivatives. Mechanistic investigations revealed that the process takes place via osmacyclopropene intermediates, which were isolated and characterized by X-ray crystallography. PMID:26368394

  13. Diverse N-Heterocyclic Ring Systems via Aza-Heck Cyclizations of N-(Pentafluorobenzoyloxy)sulfonamides

    PubMed Central

    Langer, Thomas; Bower, John F.

    2016-01-01

    Aza-Heck cyclizations initiated by oxidative addition of Pd(0)-catalysts into the N-O bond of N-(pentafluoro-benzoyloxy)sulfonamides are described. These studies, which encompass only the second class of aza-Heck reaction developed to date, provide direct access to diverse N-heterocyclic ring systems. PMID:27460965

  14. Genome-Based Discovery of an Unprecedented Cyclization Mode in Fungal Sesterterpenoid Biosynthesis.

    PubMed

    Okada, Masahiro; Matsuda, Yudai; Mitsuhashi, Takaaki; Hoshino, Shotaro; Mori, Takahiro; Nakagawa, Kazuya; Quan, Zhiyang; Qin, Bin; Zhang, Huiping; Hayashi, Fumiaki; Kawaide, Hiroshi; Abe, Ikuro

    2016-08-10

    Sesterterpenoids are a group of terpenoid natural products that are primarily biosynthesized via cyclization of the C25 linear substrate geranylfarnesyl pyrophosphate (GFPP). Although the long carbon chain of GFPP in theory allows for many different cyclization patterns, sesterterpenoids are relatively rare species among terpenoids, suggesting that many intriguing sesterterpenoid scaffolds have been overlooked. Meanwhile, the recent identification of the first sesterterpene synthase has allowed the discovery of new sesterterpenoids by the genome mining approach. In this study, we characterized the unusual fungal sesterterpene synthase EvQS and successfully obtained the sesterterpene quiannulatene (1) with a novel and unique highly congested carbon skeleton, which is further oxidized to quiannulatic acid (2) by the cytochrome P450 Qnn-P450. A mechanistic study of its cyclization from GFPP indicated that the biosynthesis employs an unprecedented cyclization mode, which involves three rounds of hydride shifts and two successive C-C bond migrations to construct the 5-6-5-5-5 fused ring system of 1. PMID:27447198

  15. Retrieving backbone string neighbors provides insights into structural modeling of membrane proteins.

    PubMed

    Sun, Jiang-Ming; Li, Tong-Hua; Cong, Pei-Sheng; Tang, Sheng-Nan; Xiong, Wen-Wei

    2012-07-01

    Identification of protein structural neighbors to a query is fundamental in structure and function prediction. Here we present BS-align, a systematic method to retrieve backbone string neighbors from primary sequences as templates for protein modeling. The backbone conformation of a protein is represented by the backbone string, as defined in Ramachandran space. The backbone string of a query can be accurately predicted by two innovative technologies: a knowledge-driven sequence alignment and encoding of a backbone string element profile. Then, the predicted backbone string is employed to align against a backbone string database and retrieve a set of backbone string neighbors. The backbone string neighbors were shown to be close to native structures of query proteins. BS-align was successfully employed to predict models of 10 membrane proteins with lengths ranging between 229 and 595 residues, and whose high-resolution structural determinations were difficult to elucidate both by experiment and prediction. The obtained TM-scores and root mean square deviations of the models confirmed that the models based on the backbone string neighbors retrieved by the BS-align were very close to the native membrane structures although the query and the neighbor shared a very low sequence identity. The backbone string system represents a new road for the prediction of protein structure from sequence, and suggests that the similarity of the backbone string would be more informative than describing a protein as belonging to a fold.

  16. SpyRings Declassified: A Blueprint for Using Isopeptide-Mediated Cyclization to Enhance Enzyme Thermal Resilience.

    PubMed

    Schoene, C; Bennett, S P; Howarth, M

    2016-01-01

    Enzymes often have marginal stability, with unfolding typically leading to irreversible denaturation. This sensitivity is a major barrier, both for de novo enzyme development and for expanding enzyme impact beyond the laboratory. Seeking an approach to enhance resilience to denaturation that could be applied to a range of different enzymes, we developed SpyRing cyclization. SpyRings contain genetically encoded SpyTag (13 amino acids) on the N-terminus and SpyCatcher (12kDa) on the C-terminus of the enzyme, so that the Spy partners spontaneously react together through an irreversible isopeptide bond. SpyRing cyclization gave major increases in thermal resilience, including on a model for enzyme evolution, β-lactamase, and an industrially important enzyme in agriculture and nutrition, phytase. We outline the SpyRing rationale, including comparison of SpyRing cyclization to other cyclization strategies. The cloning strategy is presented for the simple insertion of enzyme genes for recombinant expression. We discuss structure-based approaches to select suitable enzyme cyclization targets. Approaches to evaluate the cyclization reaction and its effect on enzyme resilience are described. We also highlight the use of differential scanning calorimetry to understand how SpyRing cyclization promotes enzyme refolding. Efficiently searching sequence space will continue to be important for enzyme improvement, but the SpyRing platform may be a valuable rational adjunct for conferring resilience. PMID:27586332

  17. Resistance of Feynman diagrams and the percolation backbone dimension.

    PubMed

    Janssen, H K; Stenull, O; Oerding, K

    1999-06-01

    We present an alternative view of Feynman diagrams for the field theory of random resistor networks, in which the diagrams are interpreted as being resistor networks themselves. This simplifies the field theory considerably as we demonstrate by calculating the fractal dimension D(B) of the percolation backbone to three loop order. Using renormalization group methods we obtain D(B)=2+epsilon/21-172epsilon(2)/9261+2epsilon(3)[-74 639+22 680zeta(3)]/4 084 101, where epsilon=6-d with d being the spatial dimension and zeta(3)=1.202 057... .

  18. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    SciTech Connect

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  19. Electron-impact total ionization cross sections of DNA sugar-phosphate backbone and an additivity principle

    NASA Technical Reports Server (NTRS)

    Huo, Winifred M.; Dateo, Christopher E.

    2005-01-01

    The improved binary-encounter dipole (iBED) model [W.M. Huo, Phys. Rev. A64, 042719-1 (2001)l is used to study the total ionization cross sections of the DNA sugar-phosphate backbone by electron impact. Calculations using neutral fragments found that the total ionization cross sections of C3' - and C5', -deoxyribose-phospate, two conformers of the sugar-phosphate backbone, are close to each other. Furthermore, the sum of the ionization cross sections of the separate deoxyribose and phosphate fragments is in close agreement with the C3' - and C5" -deoxyribose-phospate cross sections, differing by less than 10%. The result implies that certain properties of the-DNA, like the total singly ionization cross section, are localized properties and a building-up or additivity principle may apply. This allows us to obtain accurate properties of larger molecular systems built up from the results of smaller subsystem fragments. Calculations are underway using a negatively charged sugar-phosphate backbone with a metal counter-ion.

  20. Synthesis of a dialuminum-substituted silicotungstate and the diastereoselective cyclization of citronellal derivatives.

    PubMed

    Kikukawa, Yuji; Yamaguchi, Syuhei; Nakagawa, Yoshinao; Uehara, Kazuhiro; Uchida, Sayaka; Yamaguchi, Kazuya; Mizuno, Noritaka

    2008-11-26

    A novel dialuminum-substituted silicotungstate TBA(3)H[gamma-SiW(10)O(36){Al(OH(2))}(2)(mu-OH)(2)] x 4 H(2)O (1, TBA = tetra-n-butylammonium) was synthesized by the reaction of the potassium salt of [gamma-SiW(10)O(36)](8-) (SiW10) with 2 equiv of Al(NO(3))(3) in an acidic aqueous medium. It was confirmed by the X-ray crystallographic analysis that compound 1 was a monomer of the gamma-Keggin dialuminum-substituted silicotungstate with the {Al(2)(mu-OH)(2)} diamond core. The cluster framework of 1 maintained the gamma-Keggin structure in the solution states. The reaction of 1 with pyridine yielded TBA(3)[(C(5)H(5)N)H][gamma-SiW(10)O(36){Al(C(5)H(5)N)}(2)(mu-OH)(2)] x 2 H(2)O (2), and the molecular structure was successfully determined by the X-ray crystallographic analysis. In compound 2, two of three pyridine molecules coordinated to the axial positions of aluminum centers and one of them existed as a pyridinium cation, showing that compound 1 has two Lewis acid sites and one Brønsted acid site. Compound 1 showed high catalytic activity for the intramolecular cyclization of citronellal derivatives such as (+)-citronellal (3) and 3-methylcitronellal (4) without formation of byproduct resulting from etherification and dehydration. For the 1-catalyzed cyclization of 3, the diastereoselectivity toward (-)-isopulegol (3a) reached ca. 90% and the value was the highest level among those with reported systems so far. The reaction rate for the 1-catalyzed cyclization of 3 decreased by the addition of pyridine, and the cyclization hardly proceeded in the presence of 2 equiv of pyridine with respect to 1. On the other hand, the reaction rate and diastereoselectivity to 3a in the presence of 2,6-lutidine were almost the same as those in the absence. Therefore, the present cyclization is mainly promoted by the Lewis acid sites (aluminum centers) in 1. DFT calculations showed that the formation of the transition state to produce 3a is sterically and electronically more

  1. Synthesis of a dialuminum-substituted silicotungstate and the diastereoselective cyclization of citronellal derivatives.

    PubMed

    Kikukawa, Yuji; Yamaguchi, Syuhei; Nakagawa, Yoshinao; Uehara, Kazuhiro; Uchida, Sayaka; Yamaguchi, Kazuya; Mizuno, Noritaka

    2008-11-26

    A novel dialuminum-substituted silicotungstate TBA(3)H[gamma-SiW(10)O(36){Al(OH(2))}(2)(mu-OH)(2)] x 4 H(2)O (1, TBA = tetra-n-butylammonium) was synthesized by the reaction of the potassium salt of [gamma-SiW(10)O(36)](8-) (SiW10) with 2 equiv of Al(NO(3))(3) in an acidic aqueous medium. It was confirmed by the X-ray crystallographic analysis that compound 1 was a monomer of the gamma-Keggin dialuminum-substituted silicotungstate with the {Al(2)(mu-OH)(2)} diamond core. The cluster framework of 1 maintained the gamma-Keggin structure in the solution states. The reaction of 1 with pyridine yielded TBA(3)[(C(5)H(5)N)H][gamma-SiW(10)O(36){Al(C(5)H(5)N)}(2)(mu-OH)(2)] x 2 H(2)O (2), and the molecular structure was successfully determined by the X-ray crystallographic analysis. In compound 2, two of three pyridine molecules coordinated to the axial positions of aluminum centers and one of them existed as a pyridinium cation, showing that compound 1 has two Lewis acid sites and one Brønsted acid site. Compound 1 showed high catalytic activity for the intramolecular cyclization of citronellal derivatives such as (+)-citronellal (3) and 3-methylcitronellal (4) without formation of byproduct resulting from etherification and dehydration. For the 1-catalyzed cyclization of 3, the diastereoselectivity toward (-)-isopulegol (3a) reached ca. 90% and the value was the highest level among those with reported systems so far. The reaction rate for the 1-catalyzed cyclization of 3 decreased by the addition of pyridine, and the cyclization hardly proceeded in the presence of 2 equiv of pyridine with respect to 1. On the other hand, the reaction rate and diastereoselectivity to 3a in the presence of 2,6-lutidine were almost the same as those in the absence. Therefore, the present cyclization is mainly promoted by the Lewis acid sites (aluminum centers) in 1. DFT calculations showed that the formation of the transition state to produce 3a is sterically and electronically more

  2. Characterizing Aciniform Silk Repetitive Domain Backbone Dynamics and Hydrodynamic Modularity.

    PubMed

    Tremblay, Marie-Laurence; Xu, Lingling; Sarker, Muzaddid; Liu, Xiang-Qin; Rainey, Jan K

    2016-01-01

    Spider aciniform (wrapping) silk is a remarkable fibrillar biomaterial with outstanding mechanical properties. It is a modular protein consisting, in Argiope trifasciata, of a core repetitive domain of 200 amino acid units (W units). In solution, the W units comprise a globular folded core, with five α-helices, and disordered tails that are linked to form a ~63-residue intrinsically disordered linker in concatemers. Herein, we present nuclear magnetic resonance (NMR) spectroscopy-based (15)N spin relaxation analysis, allowing characterization of backbone dynamics as a function of residue on the ps-ns timescale in the context of the single W unit (W₁) and the two unit concatemer (W₂). Unambiguous mapping of backbone dynamics throughout W₂ was made possible by segmental NMR active isotope-enrichment through split intein-mediated trans-splicing. Spectral density mapping for W₁ and W₂ reveals a striking disparity in dynamics between the folded core and the disordered linker and tail regions. These data are also consistent with rotational diffusion behaviour where each globular domain tumbles almost independently of its neighbour. At a localized level, helix 5 exhibits elevated high frequency dynamics relative to the proximal helix 4, supporting a model of fibrillogenesis where this helix unfolds as part of the transition to a mixed α-helix/β-sheet fibre. PMID:27517921

  3. Error tolerant NMR backbone resonance assignment and automated structure generation.

    PubMed

    Alipanahi, Babak; Gao, Xin; Karakoc, Emre; Li, Shuai Cheng; Balbach, Frank; Feng, Guangyu; Donaldson, Logan; Li, Ming

    2011-02-01

    Error tolerant backbone resonance assignment is the cornerstone of the NMR structure determination process. Although a variety of assignment approaches have been developed, none works sufficiently well on noisy fully automatically picked peaks to enable the subsequent automatic structure determination steps. We have designed an integer linear programming (ILP) based assignment system (IPASS) that has enabled fully automatic protein structure determination for four test proteins. IPASS employs probabilistic spin system typing based on chemical shifts and secondary structure predictions. Furthermore, IPASS extracts connectivity information from the inter-residue information and the (automatically picked) (15)N-edited NOESY peaks which are then used to fix reliable fragments. When applied to automatically picked peaks for real proteins, IPASS achieves an average precision and recall of 82% and 63%, respectively. In contrast, the next best method, MARS, achieves an average precision and recall of 77% and 36%, respectively. The assignments generated by IPASS are then fed into our protein structure calculation system, FALCON-NMR, to determine the 3D structures without human intervention. The final models have backbone RMSDs of 1.25Å, 0.88Å, 1.49Å, and 0.67Å to the reference native structures for proteins TM1112, CASKIN, VRAR, and HACS1, respectively. The web server is publicly available at http://monod.uwaterloo.ca/nmr/ipass.

  4. A phylogenetic backbone for Bivalvia: an RNA-seq approach.

    PubMed

    González, Vanessa L; Andrade, Sónia C S; Bieler, Rüdiger; Collins, Timothy M; Dunn, Casey W; Mikkelsen, Paula M; Taylor, John D; Giribet, Gonzalo

    2015-02-22

    Bivalves are an ancient and ubiquitous group of aquatic invertebrates with an estimated 10 000-20 000 living species. They are economically significant as a human food source, and ecologically important given their biomass and effects on communities. Their phylogenetic relationships have been studied for decades, and their unparalleled fossil record extends from the Cambrian to the Recent. Nevertheless, a robustly supported phylogeny of the deepest nodes, needed to fully exploit the bivalves as a model for testing macroevolutionary theories, is lacking. Here, we present the first phylogenomic approach for this important group of molluscs, including novel transcriptomic data for 31 bivalves obtained through an RNA-seq approach, and analyse these data with published genomes and transcriptomes of other bivalves plus outgroups. Our results provide a well-resolved, robust phylogenetic backbone for Bivalvia with all major lineages delineated, addressing long-standing questions about the monophyly of Protobranchia and Heterodonta, and resolving the position of particular groups such as Palaeoheterodonta, Archiheterodonta and Anomalodesmata. This now fully resolved backbone demonstrates that genomic approaches using hundreds of genes are feasible for resolving phylogenetic questions in bivalves and other animals.

  5. Characterizing Aciniform Silk Repetitive Domain Backbone Dynamics and Hydrodynamic Modularity

    PubMed Central

    Tremblay, Marie-Laurence; Xu, Lingling; Sarker, Muzaddid; Liu, Xiang-Qin; Rainey, Jan K.

    2016-01-01

    Spider aciniform (wrapping) silk is a remarkable fibrillar biomaterial with outstanding mechanical properties. It is a modular protein consisting, in Argiope trifasciata, of a core repetitive domain of 200 amino acid units (W units). In solution, the W units comprise a globular folded core, with five α-helices, and disordered tails that are linked to form a ~63-residue intrinsically disordered linker in concatemers. Herein, we present nuclear magnetic resonance (NMR) spectroscopy-based 15N spin relaxation analysis, allowing characterization of backbone dynamics as a function of residue on the ps–ns timescale in the context of the single W unit (W1) and the two unit concatemer (W2). Unambiguous mapping of backbone dynamics throughout W2 was made possible by segmental NMR active isotope-enrichment through split intein-mediated trans-splicing. Spectral density mapping for W1 and W2 reveals a striking disparity in dynamics between the folded core and the disordered linker and tail regions. These data are also consistent with rotational diffusion behaviour where each globular domain tumbles almost independently of its neighbour. At a localized level, helix 5 exhibits elevated high frequency dynamics relative to the proximal helix 4, supporting a model of fibrillogenesis where this helix unfolds as part of the transition to a mixed α-helix/β-sheet fibre. PMID:27517921

  6. Relaxation of backbone bond geometry improves protein energy landscape modeling.

    PubMed

    Conway, Patrick; Tyka, Michael D; DiMaio, Frank; Konerding, David E; Baker, David

    2014-01-01

    A key issue in macromolecular structure modeling is the granularity of the molecular representation. A fine-grained representation can approximate the actual structure more accurately, but may require many more degrees of freedom than a coarse-grained representation and hence make conformational search more challenging. We investigate this tradeoff between the accuracy and the size of protein conformational search space for two frequently used representations: one with fixed bond angles and lengths and one that has full flexibility. We performed large-scale explorations of the energy landscapes of 82 protein domains under each model, and find that the introduction of bond angle flexibility significantly increases the average energy gap between native and non-native structures. We also find that incorporating bonded geometry flexibility improves low resolution X-ray crystallographic refinement. These results suggest that backbone bond angle relaxation makes an important contribution to native structure energetics, that current energy functions are sufficiently accurate to capture the energetic gain associated with subtle deformations from chain ideality, and more speculatively, that backbone geometry distortions occur late in protein folding to optimize packing in the native state.

  7. Long-term forecasting of internet backbone traffic.

    PubMed

    Papagiannaki, Konstantina; Taft, Nina; Zhang, Zhi-Li; Diot, Christophe

    2005-09-01

    We introduce a methodology to predict when and where link additions/upgrades have to take place in an Internet protocol (IP) backbone network. Using simple network management protocol (SNMP) statistics, collected continuously since 1999, we compute aggregate demand between any two adjacent points of presence (PoPs) and look at its evolution at time scales larger than 1 h. We show that IP backbone traffic exhibits visible long term trends, strong periodicities, and variability at multiple time scales. Our methodology relies on the wavelet multiresolution analysis (MRA) and linear time series models. Using wavelet MRA, we smooth the collected measurements until we identify the overall long-term trend. The fluctuations around the obtained trend are further analyzed at multiple time scales. We show that the largest amount of variability in the original signal is due to its fluctuations at the 12-h time scale. We model inter-PoP aggregate demand as a multiple linear regression model, consisting of the two identified components. We show that this model accounts for 98% of the total energy in the original signal, while explaining 90% of its variance. Weekly approximations of those components can be accurately modeled with low-order autoregressive integrated moving average (ARIMA) models. We show that forecasting the long term trend and the fluctuations of the traffic at the 12-h time scale yields accurate estimates for at least 6 months in the future.

  8. A phylogenetic backbone for Bivalvia: an RNA-seq approach

    PubMed Central

    González, Vanessa L.; Andrade, Sónia C. S.; Bieler, Rüdiger; Collins, Timothy M.; Dunn, Casey W.; Mikkelsen, Paula M.; Taylor, John D.; Giribet, Gonzalo

    2015-01-01

    Bivalves are an ancient and ubiquitous group of aquatic invertebrates with an estimated 10 000–20 000 living species. They are economically significant as a human food source, and ecologically important given their biomass and effects on communities. Their phylogenetic relationships have been studied for decades, and their unparalleled fossil record extends from the Cambrian to the Recent. Nevertheless, a robustly supported phylogeny of the deepest nodes, needed to fully exploit the bivalves as a model for testing macroevolutionary theories, is lacking. Here, we present the first phylogenomic approach for this important group of molluscs, including novel transcriptomic data for 31 bivalves obtained through an RNA-seq approach, and analyse these data with published genomes and transcriptomes of other bivalves plus outgroups. Our results provide a well-resolved, robust phylogenetic backbone for Bivalvia with all major lineages delineated, addressing long-standing questions about the monophyly of Protobranchia and Heterodonta, and resolving the position of particular groups such as Palaeoheterodonta, Archiheterodonta and Anomalodesmata. This now fully resolved backbone demonstrates that genomic approaches using hundreds of genes are feasible for resolving phylogenetic questions in bivalves and other animals. PMID:25589608

  9. SmI(2)-induced reductive cyclizations for the synthesis of cyclic ethers and applications in natural product synthesis.

    PubMed

    Nakata, Tadashi

    2010-06-01

    This tutorial review covers SmI(2)-induced reductive cyclizations of beta-alkoxyacrylate, beta-alkoxyvinyl sulfone, and beta-alkoxyvinyl sulfoxide, as methods for efficient construction of cyclic ethers. These cyclizations were developed as tools to aid in the total synthesis of marine polycyclic ethers, whose complex, synthetically challenging structures and potent bioactivities have attracted the attention of numerous synthetic organic chemists. Applications of the methods to total syntheses of various natural products containing cyclic ether are also described.

  10. Heck cyclization strategy for preparation of erythrinan alkaloids: asymmetric synthesis of unnatural (-)-erysotramidine from L-tartaric acid.

    PubMed

    Mostowicz, Danuta; Dygas, Mirosław; Kałuża, Zbigniew

    2015-02-01

    With an imide derived from L-tartaric acid as the starting material, ent-erysotramidine was synthesized for the first time. The synthesis features the use of the enantiopure synthon, prepared in a set of highly stereoselective reactions, including N-acyliminium cyclization, dihydrofuranyl ring formation via silver-catalyzed intramolecular alcohol addition to acetylene, and vinyl ether catalytic hydrogen reduction. The crucial step of the synthesis, assembly of ring A, was achieved by using Heck cyclization of (Z)-iodoolefin.

  11. Crystal Structure And Functional Analysis of Tetracenomycin Aro/Cyc: Implications for Cyclization Specificity of Aromatic Polyketides

    SciTech Connect

    Ames, B.D.; Korman, T.P.; Zhang, W.; Smith, P.; Vu, T.; Tang, Y.; Tsai, S.-C.

    2009-05-11

    Polyketides are a class of natural products with highly diverse chemical structures and pharmaceutical activities. Polyketide cyclization, promoted by the aromatase/cyclase (ARO/CYC), helps diversify aromatic polyketides. How the ARO/CYC promotes highly specific cyclization is not well understood because of the lack of a first-ring ARO/CYC structure. The 1.9 {angstrom} crystal structure of Tcm ARO/CYC reveals that the enzyme belongs to the Bet v1-like superfamily (or STAR domain family) with a helix-grip fold, and contains a highly conserved interior pocket. Docking, mutagenesis, and an in vivo assay show that the size, shape, and composition of the pocket are important to orient and specifically fold the polyketide chain for C9-C14 first-ring and C7-C16 second-ring cyclizations. Two pocket residues, R69 and Y35, were found to be essential for promoting first- and second-ring cyclization specificity. Different pocket residue mutations affected the polyketide product distribution. A mechanism is proposed based on the structure-mutation-docking results. These results strongly suggest that the regiospecific cyclizations of the first two rings and subsequent aromatizations take place in the interior pocket. The chemical insights gleaned from this work pave the foundation toward defining the molecular rules for the ARO/CYC cyclization specificity, whose rational control will be important for future endeavors in the engineered biosynthesis of novel anticancer and antibiotic aromatic polyketides.

  12. New Insights on the Mechanism of Cyclization in Chromophore Maturation of Wild-Type Green Fluorescence Protein: A Computational Study.

    PubMed

    Ma, Yingying; Zhang, Hao; Sun, Qiao; Smith, Sean C

    2016-06-23

    Cyclization is the first step in the chromophore maturation process of the green fluorescent protein (GFP). In our previous paper [J. Phys. Chem. B 2012, 116, 1426-1436], the results of molecular dynamics simulation suggested the possibility that the amide nitrogen atom of Gly67 attacks the carbonyl carbon of Ser65 directly to complete the cyclization process (one-step mechanism). In this paper, density functional theory (DFT) and quantum mechanical/molecular mechanical (QM/MM) calculations were undertaken to study this step reaction in detail. Three cluster model systems (model A, model B, and model C) and large protein system were set up to investigate the cyclization process. Our results indicate that the one-step mechanism only exists in the two minimum models. However, in model C and the large protein system, the cyclization mechanism involves two steps: the first step is proton of Gly67 amide nitrogen transferring to carbonyl oxygen of Ser65, generating protonated amide, which is stabilized by a hydrogen bond interaction with a crystallographic water molecule, and the second step is Gly67 amide nitrogen attacking the carbonyl carbon of Ser65. Arg96 plays an important role in promoting the cyclization. The energy of cyclized product relative to reactant is about 10.0 kcal/mol endothermic, which is in line with the experimental results. PMID:27232642

  13. Theoretical study of the regioselective cyclization of enaminones in the construction of benzofurans and indoles.

    PubMed

    Herrera, Rafael; Méndez, Francisco; Jiménez, Fabiola; Cruz, M Carmen; Tamariz, Joaquín

    2016-05-01

    A theoretical study was undertaken regarding the regioselective Lewis acid-promoted intramolecular cyclization of novel enaminones 1-3 leading to the corresponding benzofurans 4-5 and indoles 6. The density functional theory (DFT) and hard and soft acids and bases (HSAB) principle provided data to describe the electronic effects of the substituents in the reactivity of the benzene ring and the enaminone moiety. The condensed and local Fukui functions for nucleophilic and electrophilic attacks of the reactants accounted for the experimentally observed preference, in regard to precursors 1-3, of the cyclization between the C6' carbon (rather than the C2' carbon) of the benzene ring and the C3 center of the enaminone moiety. PMID:27132239

  14. A strategy for sequence control in vinyl polymers via iterative controlled radical cyclization

    PubMed Central

    Hibi, Yusuke; Ouchi, Makoto; Sawamoto, Mitsuo

    2016-01-01

    There is a growing interest in sequence-controlled polymers toward advanced functional materials. However, control of side-chain order for vinyl polymers has been lacking feasibility in the field of polymer synthesis because of the inherent feature of chain-growth propagation. Here we show a general and versatile strategy to control sequence in vinyl polymers through iterative radical cyclization with orthogonally cleavable and renewable bonds. The proposed methodology employs a repetitive and iterative intramolecular cyclization via a radical intermediate in a one-time template with a radical-generating site at one end and an alkene end at the other, each of which is connected to a linker via independently cleavable and renewable bonds. The unique design specifically allowed control of radical addition reaction although inherent chain-growth intermediate (radical species) was used, as well as the iterative cycle and functionalization for resultant side chains, to lead to sequence-controlled vinyl polymers (or oligomers). PMID:26996881

  15. Synthesis of heterocyclic compounds through palladium-catalyzed C-H cyclization processes.

    PubMed

    Inamoto, Kiyofumi

    2013-01-01

    Herein, we describe our development of synthetic methods for heterocyclic compounds based on the palladium-catalyzed carbon-hydrogen bond (C-H) functionalization/intramolecular carbon-heteroatom (nitrogen or sulfur) bond formation process. By this C-H cyclization method, we efficiently prepared various N-heterocycles, including indazoles, indoles, and 2-quinolinones, as well as S-heterocycles such as benzothiazoles and benzo[b]thiophenes. Yields are typically good to high and good functional-group tolerance is observed for each process, thereby indicating that the method provides a novel, highly applicable synthetic route to the abovementioned biologically important heterocyclic frameworks. As an application of this approach, an auto-tandem-type, one-pot process involving the oxidative Heck reaction and subsequent C-H cyclization using cinnamamides and arylboronic acids as starting materials in the presence of a palladium catalyst was also developed for the rapid construction of the 2-quinolinone nucleus. PMID:24088691

  16. Stereochemical requirements of oxidative cyclizations in extended iterative organoiron-mediated routes to alkaloids.

    PubMed

    Stephenson, G Richard; Roe, Caroline; Anson, Christopher E

    2012-11-01

    Oxidative cyclization by reaction of benzylic and phenolic OH groups on tricarbonyl(η(4)-cyclohexa-1,3-diene)iron(0) complexes has been achieved with the hypervalent iodine oxidant PIFA which was shown to be compatible with the tricarbonyliron complex. The reaction proceeds with substrates with the nucleophilic substituent on the opposite face of the ligand to the iron. IBX gives efficient oxidation of the benzyl alcohol to the aldehyde in the presence of the Fe(CO)(3) group. Reduction of 1-arylcyclohexadienyliron(1+) complexes with sodium borohydride to access the endo series also gave a novel rearranged 2-aryl reduction product with a 5-endo OMe group. The cis relative stereochemistry of the oxidative cyclization product, the exo delivery of hydride to the 1-arylcyclohexadienyliron(1+) complex, and the 2-aryl-5-endo-methoxy relative stereochemistry of the rearranged product were proved by X-ray crystallography.

  17. An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins.

    PubMed

    Tian, Zhenhua; Sun, Peng; Yan, Yan; Wu, Zhuhua; Zheng, Qingfei; Zhou, Shuaixiang; Zhang, Hua; Yu, Futao; Jia, Xinying; Chen, Dandan; Mándi, Attila; Kurtán, Tibor; Liu, Wen

    2015-04-01

    The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.

  18. Mechanistic insights into polycycle formation by reductive cyclization in ikarugamycin biosynthesis.

    PubMed

    Zhang, Guangtao; Zhang, Wenjun; Zhang, Qingbo; Shi, Ting; Ma, Liang; Zhu, Yiguang; Li, Sumei; Zhang, Haibo; Zhao, Yi-Lei; Shi, Rong; Zhang, Changsheng

    2014-05-01

    Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five-membered ring in ikarugamycin is reported. A three-gene-cassette ikaABC from the marine-derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five-membered ring by a Michael addition-like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs.

  19. Synthesis of an ABCD-Type Phthalocyanine by Intramolecular Cyclization Reaction.

    PubMed

    Chow, Sun Y S; Ng, Dennis K P

    2016-07-01

    Unsymmetrical phthalocyanines with a low symmetry can exhibit unique and intriguing properties that can facilitate their applications in certain disciplines. The synthesis of these compounds, however, has posed a great difficulty. A novel and unprecedented approach for phthalocyanine synthesis is reported that involves intramolecular cyclization of prelinked tetrakisphthalonitriles. By using this strategy, the first ABCD-type phthalocyanine has been prepared in 7.2% yield. PMID:27309120

  20. Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

    PubMed Central

    Czabaniuk, Lara C.; Jamison, Timothy F.

    2015-01-01

    A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium(IV) iso-propoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective endo-cyclization to form the desired tetrahydropyran ring. The HIJ ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity. PMID:25647091

  1. Thermally-Induced Substrate Release Via Intramolecular Cyclizations of Amino Esters and Amino Carbonates

    PubMed Central

    Knipp, Ralph J.; Estrada, Rosendo; Sethu, Palaniappan; Nantz, Michael H.

    2014-01-01

    The relative cleavage of an alcohol from a panel of amino esters and amino carbonates via intramolecular cyclization was examined as a mechanism for substrate release. Thermal stability at 37 °C was observed only for the 7-membered ring progenitors. Applicability of the approach was illustrated by δ-lactam formation within a poly(dimethylsiloxane) microchannel for release of a captured fluorescent probe. PMID:25061237

  2. Synthesis of an ABCD-Type Phthalocyanine by Intramolecular Cyclization Reaction.

    PubMed

    Chow, Sun Y S; Ng, Dennis K P

    2016-07-01

    Unsymmetrical phthalocyanines with a low symmetry can exhibit unique and intriguing properties that can facilitate their applications in certain disciplines. The synthesis of these compounds, however, has posed a great difficulty. A novel and unprecedented approach for phthalocyanine synthesis is reported that involves intramolecular cyclization of prelinked tetrakisphthalonitriles. By using this strategy, the first ABCD-type phthalocyanine has been prepared in 7.2% yield.

  3. Synthesis of substituted indoline and carbazole by benzyne-mediated cyclization-functionalization.

    PubMed

    Noji, Toshiharu; Fujiwara, Hideto; Okano, Kentaro; Tokuyama, Hidetoshi

    2013-04-19

    A benzyne-mediated synthesis of substituted indolines and carbazoles was developed. The reaction includes generation of benzyne using Mg(TMP)2·2LiCl as a base, cyclization, and trapping the resulting organomagnesium intermediate with an electrophile to provide a series of substituted indolines and carbazoles in a regiospecific manner. This was applied to a concise five-pot total synthesis of heptaphylline.

  4. Cyclization increases the antimicrobial activity and selectivity of arginine- and tryptophan-containing hexapeptides.

    PubMed

    Dathe, Margitta; Nikolenko, Heike; Klose, Jana; Bienert, Michael

    2004-07-20

    Arginine- and tryptophan-rich motifs have been identified in antimicrobial peptides with various secondary structures. We synthesized a set of linear hexapeptides derived from the sequence AcRRWWRF-NH(2) by substitution of tryptophan (W) by tyrosine (Y) or naphthylalanine (Nal) and by replacement of arginine (R) by lysine (K) to investigate the role of cationic charge and aromatic residues in membrane activity and selectivity. A second set of corresponding head-to-tail cyclic analogues was prepared to analyze the role of conformational constraints. The biological activity of the linear peptides followed the order Nal- > W- > Y-containing compounds and slightly decreased upon R-K substitution. A pronounced activity-improving and bacterial selectivity-enhancing effect was found upon cyclization of the R- and W-bearing parent peptide, whereas the activity-modifying effect of cyclization of Y- and Nal-containing peptides was low. The analysis of the driving forces of peptide interaction with model membranes showed that the activities correlated with the partition coefficients and the depths of peptide insertion into neutral and negatively charged lipid bilayers. Spectroscopic studies, RP-HPLC, and titration calorimetry implied that the combination of cationic and aromatic amino acid composition and conformational rigidity afforded a membrane-active, amphipathic structure with a highly charged face opposed by a cluster of aromatic side chains. However, threshold values of low and high hydrophobicity seemed to exist beyond which the activity-enhancing effect of cyclization was negligible. The results suggest that cyclization of small peptides of an appropriate amino acid composition may serve as a promising strategy in the design of antimicrobial peptides.

  5. Palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides: efficient access to C2-diversified oxazoles.

    PubMed

    Wang, Jian; Luo, Shuang; Huang, Jinbo; Mao, Tingting; Zhu, Qiang

    2014-08-25

    A novel procedure for the synthesis of C2-diversified oxazoles, through palladium-catalyzed imidoylative cyclization of α-isocyanoacetamides with aryl, vinyl, alkynyl halides, or triflates, was developed. Migratory insertion of isocyanide into a Csp3-palladium(II) intermediate in a cascade process was also realized, generating alkyl-substituted oxazoles. Therefore, oxazoles functionalized at the C2 position with sp, sp(2), and sp(3) hybridized carbon atoms are accessible by applying this method.

  6. Organocatalytic enantioselective tandem aldol-cyclization reaction of α-isothiocyanato imides and activated carbonyl compounds

    PubMed Central

    Guang, Jie; Zhao, Cong-Gui

    2011-01-01

    The organocatalytic enantioselective tandem aldol-cyclization reactions of α-isothiocyanato imides and activated carbonyl compounds, such as isatins, an α-ketolactone and a 1,2-dione, have been studied with cinchona alkaloid-derived thiourea-catalysts. This methodology provided an easy way to access enantiomerically enriched spirobicyclic thiocarbamates with high yields and good to excellent stereoselectivity, which have been demonstrated to be useful precursors for the synthesis of biologically active molecules. PMID:21921975

  7. Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes.

    PubMed

    De Simone, Filippo; Saget, Tanguy; Benfatti, Fides; Almeida, Sofia; Waser, Jérôme

    2011-12-16

    The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported. PMID:22113928

  8. Elucidating the cyclization cascades in xiamycin biosynthesis by substrate synthesis and enzyme characterizations.

    PubMed

    Li, Huixian; Sun, Yu; Zhang, Qingbo; Zhu, Yiguang; Li, Shu-Ming; Li, Ang; Zhang, Changsheng

    2015-01-16

    Indolosesquiterpene xiamycin A features a pentacyclic core structure. The chemical synthesis of two key precursors, 3-farnesylindole and 3-(epoxyfarnesyl)-indole, allowed elucidation of the enzymatic cascades forming the pentacyclic ring system of xiamycin A by XiaO-catalyzed epoxidation and the membrane protein XiaH-catalyzed terpene cyclization. The substrate flexibility of XiaI, an indole oxygenase for assembly of the central ring, was also demonstrated.

  9. Intramolecular anodic olefin coupling reactions: using competition studies to probe the mechanism of oxidative cyclization reactions.

    PubMed

    Xu, Hai-Chao; Moeller, Kevin D

    2010-04-16

    A competition experiment was designed so that the relative rates of anodic cyclization reactions under various electrolysis conditions can be determined. Reactions with ketene dithioacetal and enol ether-based substrates that use lithium methoxide as a base were shown to proceed through radical cation intermediates that were trapped by a sulfonamide anion. Results for the oxidative coupling of a vinyl sulfide with a sulfonamide anion using the same conditions were consistent with the reaction proceeding through a nitrogen-radical.

  10. Backbone dynamics of barstar: a (15)N NMR relaxation study.

    PubMed

    Sahu, S C; Bhuyan, A K; Majumdar, A; Udgaonkar, J B

    2000-12-01

    Backbone dynamics of uniformly (15)N-labeled barstar have been studied at 32 degrees C, pH 6.7, by using (15)N relaxation data obtained from proton-detected 2D (1)H-(15)N NMR spectroscopy. (15)N spin-lattice relaxation rate constants (R(1)), spin-spin relaxation rate constants (R(2)), and steady-state heteronuclear (1)H-(15)N NOEs have been determined for 69 of the 86 (excluding two prolines and the N-terminal residue) backbone amide (15)N at a magnetic field strength of 14.1 Tesla. The primary relaxation data have been analyzed by using the model-free formalism of molecular dynamics, using both isotropic and axially symmetric diffusion of the molecule, to determine the overall rotational correlation time (tau(m)), the generalized order parameter (S(2)), the effective correlation time for internal motions (tau(e)), and NH exchange broadening contributions (R(ex)) for each residue. As per the axially symmetric diffusion, the ratio of diffusion rates about the unique and perpendicular axes (D( parallel)/D( perpendicular)) is 0.82 +/- 0.03. The two results have only marginal differences. The relaxation data have also been used to map reduced spectral densities for the NH vectors of these residues at three frequencies: 0, omega(H), and omega(N), where omega(H),(N) are proton and nitrogen Larmor frequencies. The value of tau(m) obtained from model-free analysis of the relaxation data is 5.2 ns. The reduced spectral density analysis, however, yields a value of 5.7 ns. The tau(m) determined here is different from that calculated previously from time-resolved fluorescence data (4.1 ns). The order parameter ranges from 0.68 to 0.98, with an average value of 0.85 +/- 0.02. A comparison of the order parameters with the X-ray B-factors for the backbone nitrogens of wild-type barstar does not show any considerable correlation. Model-free analysis of the relaxation data for seven residues required the inclusion of an exchange broadening term, the magnitude of which ranges from 2

  11. Role of Heavy Atom Tunneling in Myers-Saito Cyclization of Cyclic Enyne-Cumulene Systems.

    PubMed

    Karmakar, Sharmistha; Datta, Ayan

    2016-02-11

    Direct dynamics calculation using canonical variational transtition state theory (CVT) inclusive of small curvature tunneling (SCT) reveals heavy atom tunneling in Myers-Saito cyclization of 10- and 9-membered cyclic enyne-cumulene systems like 1,6-didehydro[10]annulene and derivative of neocarzinostatin, respectively. The pure density functional theory functional, BLYP at a 6-31+G (d,p) basis set reproduce the observed reaction energies and barriers within 1.0 kcal/mol. The calculated rate constants of cyclization inclusive of heavy atom tunneling (k(CVT+SCT) = 3.26 × 10(-4) s(-1) at 222 K; t1/2 = 35 min) are in excellent agreement with experiments (t1/2 ∼ 21-31 min). Both primary and secondary kinetic isotope effect (KIE) become enhanced significantly upon inclusion of quantum mechanical tunneling. An Arrhenius plot of KIE shows measurable curvature at the experimental temperature of 222 K. The translation vector for the cyclization reactions in the transition-states (TS) show significant motion of primary and secondary carbon atoms explaining the origin of large KIE. PMID:26785136

  12. Intramolecular Cyclization of Thiophene-Based [7]Helicenes to Quasi-[8]Circulenes

    SciTech Connect

    Rajca, Andrzej; Miyasaka, Makoto; Xiao, Shuzhang; Boratynski, Przemystaw J.; Pink, Maren; Rajca, Suchada

    2009-12-08

    Intramolecular cyclization in a series of thiophene-based dibromo[7]helicenes (4-6) with different helix structures is investigated by vacuum pyrolysis, tin- and palladium-mediated C-C bond forming reactions. The product with the cyclic structure of the annelated aromatic rings, which resembles [8]circulene devoid of an atom linkage, is referred to as quasi-[8]circulene. Vacuum pyrolysis of 4 gives insoluble, unidentified products, while 5 and 6 yield the corresponding quasi-[8]circulenes under similar conditions. Thermogravimetry (TG) and differential scanning calorimetry (DSC) analyses for 4 indicate complex reaction pathways, while those for 5 and 6 show a single process corresponding to a loss of 1 equiv of Br2 at about 330 C. Pd-mediated reductive cyclization provides quasi-[8]circulenes for all three [7]helicenes, though only 4 gives a good isolated yield. Tributyltin hydride-mediated radical cyclization of 4-6 provides quasi-[8]circulenes in excellent yields, and it is practically insensitive to the helix structure. Experimental and calculated UV-vis absorption spectra for quasi-[8]circulenes and [8]circulenes are reported. The results suggest that the lack of atom linkage in quasi-[8]circulene does not significantly affect properties and conformation, compared to those for the corresponding [8]circulenes.

  13. Chemical characteristics and antithrombotic effect of chondroitin sulfates from sturgeon skull and sturgeon backbone.

    PubMed

    Gui, Meng; Song, Juyi; Zhang, Lu; Wang, Shun; Wu, Ruiyun; Ma, Changwei; Li, Pinglan

    2015-06-01

    Chondroitin sulfates (CSs) were extracted from sturgeon skull and backbone, and their chemical composition, anticoagulant, anti-platelet and thrombolysis activities were evaluated. The average molecular weights of CS from sturgeon skull and backbone were 38.5kDa and 49.2kDa, respectively. Disaccharide analysis indicated that the sturgeon backbone CS was primarily composed of disaccharide monosulfated in position four of the GalNAc (37.8%) and disaccharide monosulfated in position six of the GalNAc (59.6%) while sturgeon skull CS was primarily composed of nonsulfated disaccharide (74.2%). Sturgeon backbone CS showed stronger antithrombotic effect than sturgeon skull CS. Sturgeon backbone CS could significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT), inhibited ADP-induced platelet aggregation and dissolved platelet plasma clots in vitro. The results suggested that sturgeon backbone CS can be explored as a functional food with antithrombotic function.

  14. Engineering the polymer backbone to strengthen nonfouling sulfobetaine hydrogels.

    PubMed

    Carr, Louisa; Cheng, Gang; Xue, Hong; Jiang, Shaoyi

    2010-09-21

    We have demonstrated that molecularly engineering the chemical structure of a monomer can lead to hydrogels with improved mechanical strength. In this case, hydrogels from zwitterionic sulfobetaine methacrylate monomers were compared to sulfobetaine vinylimidazole (pSBVI) hydrogels. We show that the introduction of the vinylimidazole backbone improves the tensile and compressive mechanical properties of the sulfobetaine hydrogel by an order of magnitude over the same properties of a methacrylate hydrogel. Zwitterionic groups have been shown to create surface coating materials with ultralow fouling properties, and we demonstrate here that the presence of the imidazole group does not compromise the nonfouling properties attributed to the zwitterionic sulfobetaine: surfaces coated with pSBVI exhibited exceptionally low nonspecific protein adsorption, and cell adhesion was reduced by 97% relative to low-fouling poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogels. PMID:20731337

  15. Backbones of evolutionary history test biodiversity theory for microbes.

    PubMed

    O'Dwyer, James P; Kembel, Steven W; Sharpton, Thomas J

    2015-07-01

    Identifying the ecological and evolutionary mechanisms that determine biological diversity is a central question in ecology. In microbial ecology, phylogenetic diversity is an increasingly common and relevant means of quantifying community diversity, particularly given the challenges in defining unambiguous species units from environmental sequence data. We explore patterns of phylogenetic diversity across multiple bacterial communities drawn from different habitats and compare these data to evolutionary trees generated using theoretical models of biodiversity. We have two central findings. First, although on finer scales the empirical trees are highly idiosyncratic, on coarse scales the backbone of these trees is simple and robust, consistent across habitats, and displays bursts of diversification dotted throughout. Second, we find that these data demonstrate a clear departure from the predictions of standard neutral theories of biodiversity and that an alternative family of generalized models provides a qualitatively better description. Together, these results lay the groundwork for a theoretical framework to connect ecological mechanisms to observed phylogenetic patterns in microbial communities.

  16. A Native to Amyloidogenic Transition Regulated by a Backbone Trigger

    SciTech Connect

    Eakin,C.; Berman, A.; Miranker, A.

    2006-01-01

    Many polypeptides can self-associate into linear, aggregated assemblies termed amyloid fibers. High-resolution structural insights into the mechanism of fibrillogenesis are elusive owing to the transient and mixed oligomeric nature of assembly intermediates. Here, we report the conformational changes that initiate fiber formation by beta-2-microglobulin (beta2m) in dialysis-related amyloidosis. Access of beta2m to amyloidogenic conformations is catalyzed by selective binding of divalent cations. The chemical basis of this process was determined to be backbone isomerization of a conserved proline. On the basis of this finding, we designed a beta2m variant that closely adopts this intermediate state. The variant has kinetic, thermodynamic and catalytic properties consistent with its being a fibrillogenic intermediate of wild-type beta2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.

  17. Transforming plastic surfaces with electrophilic backbones from hydrophobic to hydrophilic.

    PubMed

    Kim, Samuel; Bowen, Raffick A R; Zare, Richard N

    2015-01-28

    We demonstrate a simple nonaqueous reaction scheme for transforming the surface of plastics from hydrophobic to hydrophilic. The chemical modification is achieved by base-catalyzed trans-esterification with polyols. It is permanent, does not release contaminants, and causes no optical or mechanical distortion of the plastic. We present contact angle measurements to show successful modification of several types of plastics including poly(ethylene terephthalate) (PET) and polycarbonate (PC). Its applicability to blood analysis is explored using chemically modified PET blood collection tubes and found to be quite satisfactory. We expect this approach will reduce the cost of manufacturing plastic devices with optimized wettability and can be generalized to other types of plastic materials having an electrophilic linkage as its backbone.

  18. Carbon backbone topology of the metabolome of a cell.

    PubMed

    Bingol, Kerem; Zhang, Fengli; Bruschweiler-Li, Lei; Brüschweiler, Rafael

    2012-05-30

    The complex metabolic makeup of a biological system, such as a cell, is a key determinant of its biological state providing unique insights into its function. Here we characterize the metabolome of a cell by a novel homonuclear (13)C 2D NMR approach applied to a nonfractionated uniformly (13)C-enriched lysate of E. coli cells and determine de novo their carbon backbone topologies that constitute the "topolome". A protocol was developed, which first identifies traces in a constant-time (13)C-(13)C TOCSY NMR spectrum that are unique for individual mixture components and then assembles for each trace the corresponding carbon-bond topology network by consensus clustering. This led to the determination of 112 topologies of unique metabolites from a single sample. The topolome is dominated by carbon topologies of carbohydrates (34.8%) and amino acids (45.5%) that can constitute building blocks of more complex structures. PMID:22540339

  19. Thin Films Formed from Conjugated Polymers with Ionic, Water-Soluble Backbones.

    PubMed

    Voortman, Thomas P; Chiechi, Ryan C

    2015-12-30

    This paper compares the morphologies of films of conjugated polymers in which the backbone (main chain) and pendant groups are varied between ionic/hydrophilic and aliphatic/hydrophobic. We observe that conjugated polymers in which the pendant groups and backbone are matched, either ionic-ionic or hydrophobic-hydrophobic, form smooth, structured, homogeneous films from water (ionic) or tetrahydrofuran (hydrophobic). Mismatched conjugated polymers, by contrast, form inhomogeneous films with rough topologies. The polymers with ionic backbone chains are conjugated polyions (conjugated polymers with closed-shell charges in the backbone), which are semiconducting materials with tunable bad-gaps, not unlike uncharged conjugated polymers.

  20. Proposed mechanism for the reaction catalyzed by a diterpene cyclase, aphidicolan-16beta-ol synthase: experimental results on biomimetic cyclization and examination of the cyclization pathway by ab initio calculations.

    PubMed

    Oikawa, Hideaki; Nakamura, Kensuke; Toshima, Hiroaki; Toyomasu, Tomonobu; Sassa, Takeshi

    2002-08-01

    To examine the mechanism of the cyclization reaction catalyzed by aphidicolan-16beta-ol synthase (ACS), which is a key enzyme in the biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase alpha, skeletal rearrangement of 2a and biomimetic cyclization of 4b were employed. The structures of the reaction products, which reflect penultimate cation intermediates, allowed us to propose a detailed reaction pathway for the Lewis acid-catalyzed cyclizations and rearrangements. Isolation of these products in an aphidicolin-producing fungus led us to speculate that the mechanism of the ACS-catalyzed cyclization reaction is the same as that of a nonenzymatic reaction. Ab initio calculations of the acid-catalyzed reaction intermediates and the transition states indicate that the overall reaction catalyzed by ACS is an exothermic process though the reaction proceeds via an energetically disfavored secondary cation-like transition state. In conjunction with the solvent effect in the acid-catalyzed reactions, this indicates that the actual role of ACS is to provide a template which enforces conformations of the intermediate cations leading to the productive cyclization although it has been believed that the cation-pi interaction between cation intermediates and aromatic amino acid residues in the active site is important for the enzymatic catalysis. This study provided important information on the role of various cationic species, especially secondary cation-like structures, in both nonenzymatic and enzymatic reactions.

  1. 1H, 13C, and 15N backbone, side-chain, and heme chemical shift assignments for oxidized and reduced forms of the monoheme c-type cytochrome ApcA isolated from the acidophilic metal-reducing bacterium Acidiphilium cryptum.

    SciTech Connect

    Cort, John R.; Swenson, Michael; Magnuson, Timothy S.

    2011-03-04

    We report the 1H, 13C, and 15N chemical shift assignments of both oxidized and reduced forms of an abundant periplasmic c-type cytochrome, designated ApcA, from the acidophilic gram-negative facultatively anaerobic metal-reducing alpha-proteobacterium Acidiphilium cryptum. These resonance assignments prove that ApcA is a monoheme cytochrome c2 and the product of the Acry_2099 gene. An absence of resonance peaks in the NMR spectra for the 21 N-terminal residues suggests that a predicted N-terminal signal sequence is cleaved. We also describe the preparation and purification of the protein in labeled form from laboratory cultures of A. cryptum growing on 13C- and 15N- labeled substrates.

  2. Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

    PubMed

    Luo, Dan; Callari, Roberta; Hamberger, Britta; Wubshet, Sileshi Gizachew; Nielsen, Morten T; Andersen-Ranberg, Johan; Hallström, Björn M; Cozzi, Federico; Heider, Harald; Lindberg Møller, Birger; Staerk, Dan; Hamberger, Björn

    2016-08-23

    The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon-carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids. PMID:27506796

  3. Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

    PubMed Central

    Luo, Dan; Callari, Roberta; Hamberger, Britta; Wubshet, Sileshi Gizachew; Nielsen, Morten T.; Andersen-Ranberg, Johan; Hallström, Björn M.; Cozzi, Federico; Lindberg Møller, Birger; Hamberger, Björn

    2016-01-01

    The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon–carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids. PMID:27506796

  4. Histidine-iridium(III) coordination-based peptide luminogenic cyclization and cyclo-RGD peptides for cancer-cell targeting.

    PubMed

    Ma, Xiaochuan; Jia, Junli; Cao, Rui; Wang, Xiaobo; Fei, Hao

    2014-12-24

    In the field of peptide drug discovery, structural constraining and fluorescent labeling are two sought-after techniques important for both basic research and pharmaceutical development. In this work, we describe an easy-to-use approach for simultaneous peptide cyclization and luminescent labeling based on iridium(III)-histidine coordination (Ir-HH cyclization). Using a series of model peptides with histidine flanking each terminus, the binding activity and reaction kinetics of Ir-HH cyclization of different ring sizes were characterized. In the series, Ir-HAnH (n = 2, 3) with moderate ring sizes provides appropriate flexibility and proper distance between histidines for cyclic formation, which leads to the best binding affinity and structural stability in physiological conditions, as compared to other Ir-HH-cyclized peptides with smaller (n = 0, 1) or larger (n = 4, 5) ring sizes. Ir-HRGDH, an Ir-HH-cyclized peptide containing integrin targeting motif Arg-Gly-Asp (RGD), showed better targeting affinity than its linear form and enhanced membrane permeability in comparison with fluorescein-labeled cyclic RGDyK peptide. Cell death inducing peptide KLA-linked Ir-HRGDH (Ir-HRGDH-KLA) showed dramatically enhanced cytotoxicity and high selectivity for cancer cells versus noncancer cells. These data demonstrate that the method conveniently combines structural constraining of peptides with luminescent imaging capabilities, which facilitates functional and intracellular characterization of potential peptide-based drug leads, thus introducing a new tool to meet emerging needs in medicinal research.

  5. Pendant Dynamics of Ethylene-Oxide Containing Polymers with Diverse Backbones

    NASA Astrophysics Data System (ADS)

    Bartels, Joshua; Wang, Jing-Han Helen; Chen, Quan; Runt, James; Colby, Ralph

    In the last twenty years, a wide variety of ion conducting polymers have used ether oxygens to facilitate ion conduction, and it is therefore important to understand the dynamics of ether oxygens (EOs) when attached to different polymer backbones. Four different EO-containing polymer architectures are studied by dielectric spectroscopy to understand the backbone effect on the EO dipoles. Polysiloxanes, polyphosphazenes, polymethylmethacrylates, and a polyester ether are compared, with different EO pendant lengths for the siloxane and methylmethacrylate backbones. The flexible polysiloxanes and polyphosphazene backbones impart superior segmental mobility with a glass transition temperature 15 K lower than that of the organic backbone polymers. Short EO pendants are found to impart a lower static dielectric constant at comparable EO content as compared to longer EO pendants of either inorganic or organic backbones. The long-pendant polymethylmethacrylate polymers show two relaxations corresponding to fast EOs near the pendant tail end and slow EOs close to the slower backbone, whereas the long-pendant polysiloxane shows a single relaxation due to the siloxane backbone relaxing faster than the EO pendant. Supported by the NSF Division of Materials Research Polymers Program through Grants DMR-1404586 (RHC) and DMR-1505953 (JR).

  6. The dominant folding route minimizes backbone distortion in SH3.

    PubMed

    Lammert, Heiko; Noel, Jeffrey K; Onuchic, José N

    2012-01-01

    Energetic frustration in protein folding is minimized by evolution to create a smooth and robust energy landscape. As a result the geometry of the native structure provides key constraints that shape protein folding mechanisms. Chain connectivity in particular has been identified as an essential component for realistic behavior of protein folding models. We study the quantitative balance of energetic and geometrical influences on the folding of SH3 in a structure-based model with minimal energetic frustration. A decomposition of the two-dimensional free energy landscape for the folding reaction into relevant energy and entropy contributions reveals that the entropy of the chain is not responsible for the folding mechanism. Instead the preferred folding route through the transition state arises from a cooperative energetic effect. Off-pathway structures are penalized by excess distortion in local backbone configurations and contact pair distances. This energy cost is a new ingredient in the malleable balance of interactions that controls the choice of routes during protein folding.

  7. Data Acquisition Backbone Core DABC release v1.0

    NASA Astrophysics Data System (ADS)

    Adamczewski-Musch, J.; Essel, H. G.; Kurz, N.; Linev, S.

    2010-04-01

    The Data Acquisition Backbone Core (DABC) is a general purpose software framework designed for the implementation of a wide-range of data acquisition systems - from various small detector test beds to high performance systems. DABC consists of a compact data-flow kernel and a number of plug-ins for various functional components like data inputs, device drivers, user functional modules and applications. DABC provides configurable components for implementing event building over fast networks like InfiniBand or Gigabit Ethernet. A generic Java GUI provides the dynamic control and visualization of control parameters and commands, provided by DIM servers. A first set of application plug-ins has been implemented to use DABC as event builder for the front-end components of the GSI standard DAQ system MBS (Multi Branch System). Another application covers the connection to DAQ readout chains from detector front-end boards (N-XYTER) linked to read-out controller boards (ROC) over UDP into DABC for event building, archiving and data serving. This was applied for data taking in the September 2008 test beamtime for the CBM experiment at GSI. DABC version 1.0 is released and available from the website.

  8. A New Secondary Structure Assignment Algorithm Using Cα Backbone Fragments

    PubMed Central

    Cao, Chen; Wang, Guishen; Liu, An; Xu, Shutan; Wang, Lincong; Zou, Shuxue

    2016-01-01

    The assignment of secondary structure elements in proteins is a key step in the analysis of their structures and functions. We have developed an algorithm, SACF (secondary structure assignment based on Cα fragments), for secondary structure element (SSE) assignment based on the alignment of Cα backbone fragments with central poses derived by clustering known SSE fragments. The assignment algorithm consists of three steps: First, the outlier fragments on known SSEs are detected. Next, the remaining fragments are clustered to obtain the central fragments for each cluster. Finally, the central fragments are used as a template to make assignments. Following a large-scale comparison of 11 secondary structure assignment methods, SACF, KAKSI and PROSS are found to have similar agreement with DSSP, while PCASSO agrees with DSSP best. SACF and PCASSO show preference to reducing residues in N and C cap regions, whereas KAKSI, P-SEA and SEGNO tend to add residues to the terminals when DSSP assignment is taken as standard. Moreover, our algorithm is able to assign subtle helices (310-helix, π-helix and left-handed helix) and make uniform assignments, as well as to detect rare SSEs in β-sheets or long helices as outlier fragments from other programs. The structural uniformity should be useful for protein structure classification and prediction, while outlier fragments underlie the structure–function relationship. PMID:26978354

  9. Backbone Assignment of the MALT1 Paracaspase by Solution NMR

    PubMed Central

    Unnerståle, Sofia; Nowakowski, Michal; Baraznenok, Vera; Stenberg, Gun; Lindberg, Jimmy; Mayzel, Maxim; Orekhov, Vladislav; Agback, Tatiana

    2016-01-01

    Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a unique paracaspase protein whose protease activity mediates oncogenic NF-κB signalling in activated B cell-like diffuse large B cell lymphomas (ABC-DLBCLs). ABC-DLBCLs are aggressive lymphomas with high resistance to current chemotherapies. Low survival rate among patients emphasizes the urgent need for alternative treatment options. The characterization of the MALT1 will be an essential tool for developing new target-directed drugs against MALT1 dependent disorders. As the first step in the atomic-level NMR studies of the system, here we report, the 15N/13C/1H backbone assignment of the apo form of the MALT1 paracaspase region together with the third immunoglobulin-like (Ig3) domain, 44 kDa, by high resolution NMR. In addition, the non-uniform sampling (NUS) based targeted acquisition procedure is evaluated as a mean of decreasing acquisition and analysis time for larger proteins. PMID:26788853

  10. Self-similarity of biopolymer backbones in the ribosome

    NASA Astrophysics Data System (ADS)

    Lee, Chang-Yong

    2008-08-01

    Self-similar properties of the biopolymer backbones in the ribosome are investigated in terms of the fractal dimension. We especially estimate the chain fractal and capacity dimensions of the ribosomal RNAs and proteins, which are constituents of the ribosome. The fractal dimensions of both biopolymers are compared with that of the self-avoiding walk, which is a typical model of a polymer without interaction between monomers. We demonstrate that the fractality found in the ribosomal RNAs is pertinent to explain their structural characteristics: local helix formation and long-range tertiary interaction forming three-dimensional structures. The fractal dimension of the ribosomal protein supports the existence of the long and extended domain, which is hardly seen in the globular protein. The self-similarity also upholds the fact that the ribosomal proteins function primarily to stabilize the structure of the ribosome by both the long-extended domain of the protein penetrating into the inside of the RNA, and the globular domain interacting with the RNA on the exterior of it. These results partially, if not whole, unravel the structural characteristics of the biopolymers in the ribosome.

  11. Quantitative Analysis of PMLA Nanoconjugate Components after Backbone Cleavage

    PubMed Central

    Ding, Hui; Patil, Rameshwar; Portilla-Arias, Jose; Black, Keith L.; Ljubimova, Julia Y.; Holler, Eggehard

    2015-01-01

    Multifunctional polymer nanoconjugates containing multiple components show great promise in cancer therapy, but in most cases complete analysis of each component is difficult. Polymalic acid (PMLA) based nanoconjugates have demonstrated successful brain and breast cancer treatment. They consist of multiple components including targeting antibodies, Morpholino antisense oligonucleotides (AONs), and endosome escape moieties. The component analysis of PMLA nanoconjugates is extremely difficult using conventional spectrometry and HPLC method. Taking advantage of the nature of polyester of PMLA, which can be cleaved by ammonium hydroxide, we describe a method to analyze the content of antibody and AON within nanoconjugates simultaneously using SEC-HPLC by selectively cleaving the PMLA backbone. The selected cleavage conditions only degrade PMLA without affecting the integrity and biological activity of the antibody. Although the amount of antibody could also be determined using the bicinchoninic acid (BCA) method, our selective cleavage method gives more reliable results and is more powerful. Our approach provides a new direction for the component analysis of polymer nanoconjugates and nanoparticles. PMID:25894227

  12. Backbone of complex networks of corporations: The flow of control

    NASA Astrophysics Data System (ADS)

    Glattfelder, J. B.; Battiston, S.

    2009-09-01

    We present a methodology to extract the backbone of complex networks based on the weight and direction of links, as well as on nontopological properties of nodes. We show how the methodology can be applied in general to networks in which mass or energy is flowing along the links. In particular, the procedure enables us to address important questions in economics, namely, how control and wealth are structured and concentrated across national markets. We report on the first cross-country investigation of ownership networks, focusing on the stock markets of 48 countries around the world. On the one hand, our analysis confirms results expected on the basis of the literature on corporate control, namely, that in Anglo-Saxon countries control tends to be dispersed among numerous shareholders. On the other hand, it also reveals that in the same countries, control is found to be highly concentrated at the global level, namely, lying in the hands of very few important shareholders. Interestingly, the exact opposite is observed for European countries. These results have previously not been reported as they are not observable without the kind of network analysis developed here.

  13. Backbone of complex networks of corporations: the flow of control.

    PubMed

    Glattfelder, J B; Battiston, S

    2009-09-01

    We present a methodology to extract the backbone of complex networks based on the weight and direction of links, as well as on nontopological properties of nodes. We show how the methodology can be applied in general to networks in which mass or energy is flowing along the links. In particular, the procedure enables us to address important questions in economics, namely, how control and wealth are structured and concentrated across national markets. We report on the first cross-country investigation of ownership networks, focusing on the stock markets of 48 countries around the world. On the one hand, our analysis confirms results expected on the basis of the literature on corporate control, namely, that in Anglo-Saxon countries control tends to be dispersed among numerous shareholders. On the other hand, it also reveals that in the same countries, control is found to be highly concentrated at the global level, namely, lying in the hands of very few important shareholders. Interestingly, the exact opposite is observed for European countries. These results have previously not been reported as they are not observable without the kind of network analysis developed here.

  14. Synthesis of a 7-Azaindole by Chichibabin Cyclization: Reversible Base-Mediated Dimerization of 3-Picolines

    PubMed Central

    Ma, Yun; Breslin, Sean; Keresztes, Ivan; Lobkovsky, Emil; Collum, David B.

    2009-01-01

    The lithium diisopropylamide (LDA)-mediated condensation of 2-fluoro-3-picoline and benzonitrile to form 2-phenyl-7-azaindole via a Chichibabin cyclization is described. Facile dimerization of the picoline via a 1,4-addition of the incipient benzyllithium to the picoline starting material and fast 1,2-addition of LDA to benzonitrile cause the reaction to be complex. Both adducts are shown to reenter the reaction coordinate to produce the desired 7-azaindole. The solution structures of the key intermediates and the underlying reaction mechanisms are studied by a combination of IR and NMR spectroscopies. PMID:18707175

  15. Raman spectroscopic approach to monitor the in vitro cyclization of creatine → creatinine

    NASA Astrophysics Data System (ADS)

    Gangopadhyay, Debraj; Sharma, Poornima; Singh, Sachin Kumar; Singh, Pushkar; Tarcea, Nicolae; Deckert, Volker; Popp, Jürgen; Singh, Ranjan K.

    2015-01-01

    The creatine → creatinine cyclization, an important metabolic phenomenon has been initiated in vitro at acidic pH and studied through Raman spectroscopic and DFT approach. The equilibrium composition of neutral, zwitterionic and protonated microspecies of creatine has been monitored with time as the reaction proceeds. Time series Raman spectra show clear signature of creatinine formation at pH 3 after ∼240 min at room temperature and reaction is faster at higher temperature. The spectra at pH 1 and pH 5 do not show such signature up to 270 min implying faster reaction rate at pH 3.

  16. Base-Controlled Cu-Catalyzed Tandem Cyclization/Alkynylation for the Synthesis of Indolizines.

    PubMed

    Oh, Kyung Hwan; Kim, Seong Min; Park, Sun Young; Park, Jin Kyoon

    2016-05-01

    A base-controlled Cu-catalyzed tandem cyclization/alkynylation of propargylic amines provides rapid access to functionalized indolizine derivatives under mild reaction conditions. The reaction first proceeded via a 5-endo-dig aminocupration, followed by a coupling between the copper-bound intermediate and alkynyl bromide, to afford the products in good to excellent yields. The successful tandem reaction is attributed to the unique property of the bases, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene used). PMID:27097044

  17. Stereocontrolled synthesis of rosuvastatin calcium via iodine chloride-induced intramolecular cyclization.

    PubMed

    Xiong, Fangjun; Wang, Haifeng; Yan, Lingjie; Han, Sheng; Tao, Yuan; Wu, Yan; Chen, Fener

    2016-01-28

    A novel, stereoselective approach towards rosuvastatin calcium from the known (S)-homoallylic alcohol has been developed. The synthesis is highlighted by a regio- and stereocontrolled ICl-induced intramolecular cyclization of chiral homoallylic carbonate to deliver the C6-formyl statin side chain with a syn-1,3-diol moiety. An improved synthesis of the rosuvastatin pyrimidine core moiety is also included. Moreover, this methodology is useful in the asymmetric synthesis of structural variants of statins such as pitavastatin calcium and atorvastatin calcium and their related analogs.

  18. 5-Exo-cyclizations of pentenyliminyl radicals: inversion of the gem-dimethyl effect.

    PubMed

    Portela-Cubillo, Fernando; Alonso-Ruiz, Rafael; Sampedro, Diego; Walton, John C

    2009-09-17

    This paper describes how the rates of 5-exo-ring closures of unsaturated iminyl radicals to pyrrolomethyl radicals respond to substituents in the pentenyl chain and at the C=N bond. Benzyl- and acyl oxime esters, as well as dioxime oxalates, were identified as suitable iminyl radical sources for electron paramagnetic resonance (EPR) spectroscopy. Pentenyliminyl radicals with aryl substituents at their C=N bonds, and one with an alkyl substituent at its C=N bond, were studied in solution by steady-state continuous wave EPR spectroscopy. All the pentenyliminyls selectively ring closed in the 5-exo-mode rather than the 6-endo-mode. EPR monitoring of the decay of the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical showed that it underwent bimolecular combination at about the diffusion controlled limit (2kt approximately 3 x 10(8) M(-1) s(-1) at 245 K). The rate constant for 5-exo-ring closure of phenylpentenyliminyl (8.8 x 10(3) s(-1) at 300 K) was a factor of 25 smaller than the rate constant for hex-5-enyl radical cyclization. The rate of cyclization was slower for an iminyl having a Me group at the site of 5-exo-cyclization but faster for an iminyl with an Et substituent at the terminus of the C=C double bond. Surprisingly, the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical, with a bismethyl group in its pentenyl chain, ring closed more slowly than the unsubstituted analogue. DFT computations were in accord with this inverse gem-dimethyl effect and suggested it resulted from steric interaction of the Ph and bis-Me groups which forced the aromatic ring out of the plane of the imine moiety. To check on the role of the Ph substituent, pentenyliminyls lacking this group were sought. A pentenyliminyl radical with an alkyl group in place of the Ph group, and a single Me group in its pentenyl chain, was generated by means of an unsymmetrical dioxime oxalate precursor. The k(c) for this species was a factor of 2.5 larger than k(c) for the original pentenyliminyl, suggesting

  19. 5-Exo-Cyclizations of Pentenyliminyl Radicals: Inversion of the gem-Dimethyl Effect

    NASA Astrophysics Data System (ADS)

    Portela-Cubillo, Fernando; Alonso-Ruiz, Rafael; Sampedro, Diego; Walton, John C.

    2009-08-01

    This paper describes how the rates of 5-exo-ring closures of unsaturated iminyl radicals to pyrrolomethyl radicals respond to substituents in the pentenyl chain and at the C═N bond. Benzyl- and acyl oxime esters, as well as dioxime oxalates, were identified as suitable iminyl radical sources for electron paramagnetic resonance (EPR) spectroscopy. Pentenyliminyl radicals with aryl substituents at their C═N bonds, and one with an alkyl substituent at its C═N bond, were studied in solution by steady-state continuous wave EPR spectroscopy. All the pentenyliminyls selectively ring closed in the 5-exo-mode rather than the 6-endo-mode. EPR monitoring of the decay of the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical showed that it underwent bimolecular combination at about the diffusion controlled limit (2kt ˜ 3 × 108 M-1 s-1 at 245 K). The rate constant for 5-exo-ring closure of phenylpentenyliminyl (8.8 × 103 s-1 at 300 K) was a factor of 25 smaller than the rate constant for hex-5-enyl radical cyclization. The rate of cyclization was slower for an iminyl having a Me group at the site of 5-exo-cyclization but faster for an iminyl with an Et substituent at the terminus of the C═C double bond. Surprisingly, the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical, with a bismethyl group in its pentenyl chain, ring closed more slowly than the unsubstituted analogue. DFT computations were in accord with this inverse gem-dimethyl effect and suggested it resulted from steric interaction of the Ph and bis-Me groups which forced the aromatic ring out of the plane of the imine moiety. To check on the role of the Ph substituent, pentenyliminyls lacking this group were sought. A pentenyliminyl radical with an alkyl group in place of the Ph group, and a single Me group in its pentenyl chain, was generated by means of an unsymmetrical dioxime oxalate precursor. The kc for this species was a factor of 2.5 larger than kc for the original pentenyliminyl, suggesting that the normal

  20. Rates of Hexadehydro-Diels–Alder (HDDA) Cyclizations: Impact of the Linker Structure

    PubMed Central

    2015-01-01

    The rates of the hexadehydro-Diels–Alder (HDDA) reaction of substrates containing, minimally, a 1,3,8-triyne subunit are reported. Several series of related substrates, differing in the nature of the three-atom tether that links the 1,3-diyne and diynophile, were examined. Seemingly small changes in substrate structure result in large differences in cyclization rate, spanning more than 8 orders of magnitude. The reactivity trends revealed by these studies should prove useful in guiding substrate design and choice of reaction conditions in future applications. PMID:25153729

  1. Synthesis of functionalized indole- and benzo-fused heterocyclic derivatives through anionic benzyne cyclization.

    PubMed

    Barluenga, José; Fañanás, Francisco J; Sanz, Roberto; Fernández, Yolanda

    2002-05-01

    The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.

  2. Synthesis of Substituted Pyrroles via Copper-Catalyzed Cyclization of Ethyl Allenoates with Activated Isocyanides.

    PubMed

    Lu, Kui; Ding, Fang; Qin, Long; Jia, Xiaoliang; Xu, Chuanming; Zhao, Xia; Yao, Qingwei; Yu, Peng

    2016-08-01

    A new method for the synthesis of di- and trisubstituted pyrroles via copper-catalyzed cyclization of ethyl allenoates with activated isocyanides has been developed. In contrast to related annulation reactions previously reported, this new process features a skeletal rearrangement in which the aryl sulfonyl moiety, which functions as the electron-withdrawing group in the α-carbon of the isocyanide, was found to migrate to the γ-carbon of the starting allenoate in the final product for the first time. PMID:27348611

  3. Palladium-catalyzed intramolecular cyclization of ynamides: synthesis of 4-halo-oxazolones.

    PubMed

    Huang, Hai; He, Guangke; Zhu, Guohao; Zhu, Xiaolin; Qiu, Shineng; Zhu, Hongjun

    2015-04-01

    A mild and efficient methodology involving Pd(PPh3)4-catalyzed intramolecular cyclization of N-alkynyl alkyloxycarbamates with CuCl2 or CuBr2 for the synthesis of 4-halo-oxazolones was developed. This reaction exhibiting good functional tolerance provided a new, efficient, and rapid synthetic process to 4-halo-oxazolones. The resulting 4-halo-oxazolones can serve as great potential precursors for the 3,4,5-trisubstituted oxazolones via a Pd-catalyzed cross-coupling reaction.

  4. Copper-catalyzed synthesis of benzoxazoles via tandem cyclization of 2-halophenols with amidines.

    PubMed

    Tiwari, Abhishek R; Bhanage, Bhalchandra M

    2016-08-16

    This work reports a simple, efficient and alternative synthetic route for the preparation of benzoxazoles via tandem cyclization of 2-halophenols with amidines. The developed methodology is free from ligands and uses inexpensive and easily available CuCl as a catalyst. This protocol avoids the use of any oxidant or inorganic acids. Various benzoxazole derivatives were synthesized in good to excellent yields. To the best of our knowledge, this is the first time that the synthesis of benzoxazoles from 2-halophenols with both aromatic and aliphatic amidines is reported. Owing to the simplicity of this protocol, the preparation of benzoxazoles could be achieved at a gram scale level. PMID:27480248

  5. Exploration of Cascade Cyclizations Terminated By Tandem Aromatic Substitution: Total Synthesis of (+)-Schweinfurthin A

    PubMed Central

    Topczewski, Joseph J.; Kodet, John G.; Wiemer, David F.

    2011-01-01

    The termination of epoxide-initiated cascade cyclizations with a range of “protected” phenols is described. When the protecting group can be lost as a stabilized electrophile, the cascade process continues beyond ring closure to afford products which have undergone a tandem electrophilic aromatic substitution. A number of groups have proven viable in this process and the regiochemistry of their substitution reactions has been studied. Application of this methodology in the first total synthesis of (+)-schweinfurthin A, a potent anti-proliferative agent, has been achieved. PMID:21226493

  6. Approach to Merosesquiterpenes via Lewis Acid Catalyzed Nazarov-Type Cyclization: Total Synthesis of Akaol A.

    PubMed

    Kakde, Badrinath N; Kumar, Nivesh; Mondal, Pradip Kumar; Bisai, Alakesh

    2016-04-15

    A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)2 and Bi(OTf)3 in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine sesquiterpene quinol, akaol A (1a). PMID:27028314

  7. Catalytic Asymmetric Nazarov Cyclization of Heteroaryl Vinyl Ketones through a Crystallographically Defined Chiral Dinuclear Nickel Complex.

    PubMed

    Takeda, Takuya; Harada, Shinji; Nishida, Atsushi

    2015-11-01

    A Ni(NTf2)2 and tetradentate bisimino-bisquinoline ligand complex catalyzed the enantioselective Nazarov cyclization of heteroaryl vinyl ketones. An X-ray-quality crystal was obtained from a mixture of the Ni complex and the substrate, which was the dinuclear chiral Ni complex. From information regarding the structure of the complex, the substrate was distorted to form a helical shape, and the carbon atoms involved in bond formation were close to each other. In addition, mechanistic studies revealed that the configuration of the olefin moiety was isomerized before bond formation. PMID:26466157

  8. Efficient one-pot cyclization/folding of Rhesus θ-defensin-1 (RTD-1)

    PubMed Central

    Aboye, Teshome L.; Li, Yilong; Majumder, Subhabrata; Hao, Jinfeng; Shekhtman, Alexander; Camarero, Julio A.

    2012-01-01

    We report an efficient approach for the chemical synthesis of Rhesus θ-defensin-1 (RTD-1) using Fmoc-based solid-phase peptide synthesis in combination with an intramolecular version of native chemical ligation. The corresponding linear thioester precursor was cyclized and folded in a one-pot reaction using reduced glutathione. The reaction was extremely efficiently yielding natively folded RTD-1 with minimal or no purification at all. This approach is fully compatible with the high throughput production of chemical libraries using this peptide scaffold. PMID:22425570

  9. Efficient one-pot synthesis of 5-perfluoroalkylpyrazoles by cyclization of hydrazone dianions.

    PubMed

    Ngo, Thang Ngoc; Ejaz, Syeda Abida; Hung, Tran Quang; Dang, Tuan Thanh; Iqbal, Jamshed; Lecka, Joanna; Sévigny, Jean; Langer, Peter

    2015-08-14

    A highly selective and efficient method for the synthesis of 5-trifluoromethylated and 5-perfluoroalkylated pyrazoles has been developed which relies on the cyclization of hydrazine dianions with ethyl perfluorocarboxylates. The pyrazoles prepared were evaluated as potential inhibitors of alkaline phosphatases, namely human tissue non-specific alkaline phosphatase (h-TNAP) and tissue specific intestinal alkaline phosphatase (IAP). Most pyrazole derivatives inhibited h-IAP more markedly than h-TNAP and had minor effects on nucleotide pyrophosphatase/phosphodiesterases. Therefore, the compounds appear as potential selective inhibitors of h-IAP.

  10. Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis.

    PubMed

    Williams, Katherine; Szwalbe, Agnieszka J; Mulholland, Nicholas P; Vincent, Jason L; Bailey, Andrew M; Willis, Christine L; Simpson, Thomas J; Cox, Russell J

    2016-06-01

    Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins. PMID:27099957

  11. Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

    PubMed Central

    Szwalbe, Agnieszka J.; Mulholland, Nicholas P.; Vincent, Jason L.; Bailey, Andrew M.; Willis, Christine L.; Simpson, Thomas J.

    2016-01-01

    Abstract Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9‐membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate‐processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine‐binding proteins. PMID:27099957

  12. Octupolar (C3 and S4) Symmetric Cyclized Indole Derivatives: Syntheses, Structures, and NLO Properties.

    PubMed

    Wang, Lei; Fang, Qi; Lu, Qing; Zhang, Shao-jun; Jin, Ying-ying; Liu, Zhi-qiang

    2015-09-01

    Several cyclized indole derivatives have been synthesized, and their structures been determined. The C3-symmetric single-chiral N-phenyltriindole (Tr-Ph3) crystallized in the P1 space group, and the S4-symmetric saddle-like tetraindole (TTr) crystallized in the I4̅ space group. The Tr-Ph3 and TTr crystals exhibit remarkable powder SHG intensities 5 and 11 times that of KH2PO4 (KDP), respectively. TTr is a useful octupolar core to build S4-symmetric molecules and crystals for second-NLO materials.

  13. Copper-catalyzed intramolecular cyclization of N-propargyl-adenine: synthesis of purine-fused tricyclics.

    PubMed

    Li, Ren-Long; Liang, Lei; Xie, Ming-Sheng; Qu, Gui-Rong; Niu, Hong-Ying; Guo, Hai-Ming

    2014-04-18

    A novel protocol to construct fluorescent purine-fused tricyclic products via intramolecular cyclization of N-propargyl-adenine has been developed. With CuBr as the catalyst, a series of purine-fused tricyclic products were obtained in good to excellent yields (19 examples, 75-89% yields). When R2 was a hydrogen atom in N-propargyl-adenines, the reactions only afforded the endocyclic double bond products. When R2 was an aryl group, the electron-donating groups favored the endocyclic double bond products, while the electron-withdrawing groups favored the exocyclic double bond products. PMID:24678722

  14. The polysiloxane cyclization equilibrium constant: a theoretical focus on small and intermediate size rings.

    PubMed

    Madeleine-Perdrillat, Claire; Delor-Jestin, Florence; de Sainte Claire, Pascal

    2014-01-01

    The nonlinear dependence of polysiloxane cyclization constants (log(K(x))) with ring size (log(x)) is explained by a thermodynamic model that treats specific torsional modes of the macromolecular chains with a classical coupled hindered rotor model. Several parameters such as the dependence of the internal rotation kinetic energy matrix with geometry, the effect of potential energy hindrance, anharmonicity, and the couplings between internal rotors were investigated. This behavior arises from the competing effects of local molecular entropy that is mainly driven by the intrinsic transformation of vibrations in small cycles into hindered rotations in larger cycles and configurational entropy.

  15. Structure and backbone dynamics of a microcrystalline metalloprotein by solid-state NMR.

    PubMed

    Knight, Michael J; Pell, Andrew J; Bertini, Ivano; Felli, Isabella C; Gonnelli, Leonardo; Pierattelli, Roberta; Herrmann, Torsten; Emsley, Lyndon; Pintacuda, Guido

    2012-07-10

    We introduce a new approach to improve structural and dynamical determination of large metalloproteins using solid-state nuclear magnetic resonance (NMR) with (1)H detection under ultrafast magic angle spinning (MAS). The approach is based on the rapid and sensitive acquisition of an extensive set of (15)N and (13)C nuclear relaxation rates. The system on which we demonstrate these methods is the enzyme Cu, Zn superoxide dismutase (SOD), which coordinates a Cu ion available either in Cu(+) (diamagnetic) or Cu(2+) (paramagnetic) form. Paramagnetic relaxation enhancements are obtained from the difference in rates measured in the two forms and are employed as structural constraints for the determination of the protein structure. When added to (1)H-(1)H distance restraints, they are shown to yield a twofold improvement of the precision of the structure. Site-specific order parameters and timescales of motion are obtained by a gaussian axial fluctuation (GAF) analysis of the relaxation rates of the diamagnetic molecule, and interpreted in relation to backbone structure and metal binding. Timescales for motion are found to be in the range of the overall correlation time in solution, where internal motions characterized here would not be observable.

  16. Variants of the prins cyclization for the synthesis of terpenoid spiroethers and oxabicyclo[3.3.1]nonane derivatives.

    PubMed

    Weidmann, Verena; Ploog, Jasper; Kliewer, Serge; Schaffrath, Mathias; Maison, Wolfgang

    2014-11-01

    Terpenoid spiroethers are abundant natural flavors with significant impact, particularly in the food industry. We present in this article the synthesis of new derivatives of the well-known flavors theaspirane and vitispirane using a variant of the Prins cyclization starting from α,β-unsaturated or heterocyclic ketones. When aromatic ketones were used as the starting materials for Lewis acid-mediated cyclizations, an alternative pathway involving a domino sequence of Prins cyclization, followed by an intramolecular Friedel-Crafts alkylation, gave benzoannelated oxabicyclo[3.3.1]nonane derivatives. Different reaction pathways may be triggered by the reaction temperature to give with good selectivity either tetrahydropyran derivatives as conventional Prins products or oxabicyclo[3.3.1]nonane derivatives. PMID:25303120

  17. Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery.

    PubMed

    Reichart, Florian; Horn, Mareike; Neundorf, Ines

    2016-06-01

    In this work we report synthesis and biological evaluation of a cell-penetrating peptide (CPP), that is partly cyclized via a triazole bridge. Recently, beneficious properties have been reported for cyclized peptides concerning their metabolic stability and intracellular uptake. A CPP based on human calcitonin was used in this study, and side chain cyclization was achieved via copper catalyzed alkyne-azide click reaction. Cell viability studies in several cell-lines revealed no cytotoxic effects. Furthermore, efficient uptake in breast cancer MCF-7 cells could be determined. Moreover, preliminary studies using this novel peptide as drug transporter for daunorubicin were performed. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27197760

  18. Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N-O bond-forming cyclization of 2-azidobenzoic acids.

    PubMed

    Dzhons, Daria Yu; Budruev, Andrei V

    2016-01-01

    The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions.

  19. Visible light-induced intramolecular dearomative cyclization of α-bromo-N-benzyl-alkylamides: efficient construction of 2-azaspiro[4.5]decanes.

    PubMed

    Hu, Bei; Li, Yuyuan; Dong, Wuheng; Ren, Kai; Xie, Xiaomin; Wan, Jun; Zhang, Zhaoguo

    2016-03-01

    An efficient intramolecular dearomative cyclization via visible light-induced photoredox catalysis allows for a highly regioselective dearomative cyclization of α-bromo-N-benzyl-alkylamides to construct 2-azaspiro[4.5]decanes in the presence of an iridium catalyst. PMID:26865333

  20. Synthesis of 2,1-benzisoxazole-3(1H)-ones by base-mediated photochemical N–O bond-forming cyclization of 2-azidobenzoic acids

    PubMed Central

    Dzhons, Daria Yu

    2016-01-01

    Summary The base-mediated photochemical cyclization of 2-azidobenzoic acids with the formation of 2,1-benzisoxazole-3(1H)-ones is reported. The optimization and scope of this cyclization reaction is discussed. It is shown that an essential step of the ring closure of 2-azidobenzoic acids is the formation and photolysis of 2-azidobenzoate anions. PMID:27340478

  1. Copper-catalyzed cascade cyclization of 1,7-enynes with aromatic sulfonyl chlorides toward selective assembly of benzo[j]phenanthridin-6(5H)-ones.

    PubMed

    Liu, Yu; Zhang, Jia-Ling; Zhou, Ming-Bo; Song, Ren-Jie; Li, Jin-Heng

    2014-11-28

    A step-economical method for the cascade cyclization of 1,7-enynes with aromatic sulfonyl chlorides by using a low-cost and more abundant Cu catalyst is presented. This method allows access to benzo[j]phenanthridin-6(5H)-ones and represents a new Cu-catalyzed cascade cyclization of 1,n-enynes. PMID:25300349

  2. Pseudo 5D HN(C)N experiment to facilitate the assignment of backbone resonances in proteins exhibiting high backbone shift degeneracy

    NASA Astrophysics Data System (ADS)

    Kumar, Dinesh; Raikwal, Nisha; Shukla, Vaibhav Kumar; Pandey, Himanshu; Arora, Ashish; Guleria, Anupam

    2014-09-01

    Assignment of protein backbone resonances is most routinely carried out using triple resonance three-dimensional NMR experiments involving amide 1H/15N resonances. However for intrinsically unstructured proteins, alpha-helical proteins or proteins containing several disordered fragments, the assignment becomes problematic because of high-degree of backbone shift degeneracy. In this backdrop, a novel reduced-dimensionality (RD) experiment -(5, 3)D-hNCO-CANH- is presented to facilitate/validate the sequential backbone resonance assignment in such proteins. The proposed 3D NMR experiment makes use of the modulated amide 15N chemical shifts (resulting from the joint sampling along both its indirect dimensions) to resolve the ambiguity involved in connecting the neighboring amide resonances (i.e. HiNi and Hi-1Ni-1) for overlapping amide-NH peaks. The experiment -in combination with routine triple resonance 3D-NMR experiments involving backbone amide (1H/15N) and carbon (13Cα/13C‧) chemical shifts- will serve as a powerful complementary tool to achieve the nearly complete assignment of protein backbone resonances in a time efficient manner.

  3. Solution structure and backbone dynamics of the defunct domain of calcium vector protein.

    PubMed

    Théret, I; Baladi, S; Cox, J A; Gallay, J; Sakamoto, H; Craescu, C T

    2001-11-20

    CaVP (calcium vector protein) is a Ca(2+) sensor of the EF-hand protein family which is highly abundant in the muscle of Amphioxus. Its three-dimensional structure is not known, but according to the sequence analysis, the protein is composed of two domains, each containing a pair of EF-hand motifs. We determined recently the solution structure of the C-terminal domain (Trp81-Ser161) and characterized the large conformational and dynamic changes induced by Ca(2+) binding. In contrast, the N-terminal domain (Ala1-Asp86) has lost the capacity to bind the metal ion due to critical mutations and insertions in the two calcium loops. In this paper, we report the solution structure of the N-terminal domain and its backbone dynamics based on NMR spectroscopy, nuclear relaxation, and molecular modeling. The well-resolved three-dimensional structure is typical of a pair of EF-hand motifs, joined together by a short antiparallel beta-sheet. The tertiary arrangement of the two EF-hands results in a closed-type conformation, with near-antiparallel alpha-helices, similar to other EF-hand pairs in the absence of calcium ions. To characterize the internal dynamics of the protein, we measured the (15)N nuclear relaxation rates and the heteronuclear NOE effect in (15)N-labeled N-CaVP at a magnetic field of 11.74 T and 298 K. The domain is mainly monomeric in solution and undergoes an isotropic Brownian rotational diffusion with a correlation time of 7.1 ns, in good agreement with the fluorescence anisotropy decay measurements. Data analysis using a model-free procedure showed that the amide backbone groups in the alpha-helices and beta-strands undergo highly restricted movements on a picosecond to nanosecond time scale. The amide groups in Ca(2+) binding loops and in the linker fragment also display rapid fluctuations with slightly increased amplitudes. PMID:11705378

  4. Synthesis of polyhydroxylated pyrrolidines from sugar-derived bromonitriles through a cascade addition of allylmagnesium bromide/cyclization/reduction.

    PubMed

    Malik, Michał; Jarosz, Sławomir

    2016-02-01

    The synthesis of polyhydroxylated 2-allylpyrrolidines from sugar-derived bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/reduction with Zn(BH4)2 is described. The stereochemical course of the reduction step is rationalized. Two of the obtained compounds are transformed into stereoisomers of naturally-occurring iminosugar (+)-lentiginosine. In an alternative approach, 2,2-diallylpyrrolidines are obtained from bromonitriles in a cascade addition of allylmagnesium bromide/SN2 cyclization/addition of another equivalent of allylmagnesium bromide.

  5. Highly stereoselective construction of spiro[4.5]decanes by SmI(2)-promoted ketyl radical mediated tandem cyclization.

    PubMed

    Inui, Masaharu; Nakazaki, Atsuo; Kobayashi, Susumu

    2007-02-01

    [reaction: see text] Ketyl radical mediated tandem cyclization of omega-alkynyl carbonyl compounds bearing activated alkene using SmI(2) gave spiro[4.5]decanes stereoselectively. In the presence of HMPA, alpha,beta-unsaturated esters and alkenyl phosphonates were converted to spiro[4.5]decanes and a monocyclic compound, respectively. In the presence of Sm, bicyclic lactones were obtained from alpha,beta-unsaturated esters. The spiro[4.5]decane was provided from an alkenyl phosphonate. Interestingly, the stereochemical changeover at the first cyclization has been controlled by means of a variety of activators.

  6. Calcium-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols Derived from Donor-Acceptor Cyclopropanes.

    PubMed

    Sandridge, Matthew J; France, Stefan

    2016-09-01

    A calcium-catalyzed, dehydrative, ring-opening cyclization of (hetero)aryl cyclopropyl carbinols is reported. The cyclopropyl carbinols are prepared directly from the corresponding donor-acceptor (D-A) cyclopropanes. The calcium catalyst catalyzes the formation of putative (hetero)aryl cyclopropyl carbinyl cations that undergo ring-opening to allylcarbinyl cations. Subsequent intramolecular Friedel-Crafts reaction affords (hetero)aryl-fused cyclohexa-1,3-dienes in up to 97% yield. This approach represents the first example of catalysis for this intramolecular, dehydrative ring-opening cyclization and outperforms the previous reports using stoichiometric Lewis acids. PMID:27517711

  7. Catalytic, Interrupted Formal Homo-Nazarov Cyclization with (Hetero)arenes: Access to α-(Hetero)aryl Cyclohexanones.

    PubMed

    Williams, Corey W; Shenje, Raynold; France, Stefan

    2016-09-16

    The first examples of a Lewis-acid catalyzed (hetero)arene interrupted, formal homo-Nazarov cyclization have been disclosed. Using SnCl4 as the catalyst, alkenyl cyclopropyl ketones undergo ring-opening cyclization to form six-membered cyclic oxyallyl cations. Subsequent intermolecular Friedel-Crafts-type arylation with various electron-rich arenes and heteroarenes provides functionalized α-(hetero)arylated cyclohexanones, a scaffold present in many natural products and bioactive compounds, in yields up to 88% and diastereomeric ratios up to 12:1. Regiospecific arylation occurs at the α-carbon of the oxyallyl cation due to polarization caused by the ester group. PMID:27529123

  8. Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes.

    PubMed

    Zhang, Jun; Song, Shangfei; Wang, Xiao; Jiao, Jiajun; Shi, Min

    2013-10-21

    Three ruthenium complexes bearing backbone-monosubstituted CAACs were prepared and displayed dramatic improvement in catalytic efficiency not only in RCM reaction but also in the ethenolysis of methyl oleate, compared to those bearing backbone-disubstituted CAACs. PMID:24013192

  9. Ruthenium-catalyzed olefin metathesis accelerated by the steric effect of the backbone substituent in cyclic (alkyl)(amino) carbenes.

    PubMed

    Zhang, Jun; Song, Shangfei; Wang, Xiao; Jiao, Jiajun; Shi, Min

    2013-10-21

    Three ruthenium complexes bearing backbone-monosubstituted CAACs were prepared and displayed dramatic improvement in catalytic efficiency not only in RCM reaction but also in the ethenolysis of methyl oleate, compared to those bearing backbone-disubstituted CAACs.

  10. Lewis super-acid catalyzed cyclizations: a new route to fragrance compounds.

    PubMed

    Coulombel, Lydie; Grau, Fanny; Weïwer, Michel; Favier, Isabelle; Chaminade, Xavier; Heumann, Andreas; Bayón, J Carles; Aguirre, Pedro A; Duñach, Elisabet

    2008-06-01

    This review deals with the application of Lewis super acids such as Al(III), In(III), and Sn(IV) triflates and triflimidates as catalysts in the synthesis of fragrance materials. Novel catalytic reactions involving C-C and C-heteroatom bond-forming reactions, as well as cycloisomerization processes are presented. In particular, Sn(IV) and Al(III) triflates were employed as catalysts in the selective cyclization of unsaturated alcohols to cyclic ethers, as well as in the cyclization of unsaturated carboxylic acids to lactones. The addition of thiols and thioacids to non-activated olefins, both in intra- and intermolecular versions, was efficiently catalyzed by In(III) derivatives. Sn(IV) Triflimidates catalyzed the cycloisomerization of highly substituted 1,6-dienes to gem-dimethyl-substituted cyclohexanes bearing an isopropylidene substituent. The hydroformylation of these unsaturated substrates, catalyzed by a Rh(I) complex with a bulky phosphite ligand, selectively afforded the corresponding linear aldehydes. The olfactory evaluation of selected heterocycles, carbocycles, and aldehydes synthesized is also discussed.

  11. Iron(III)-catalyzed cyclization of alkynyl aldehyde acetals: experimental and computational studies.

    PubMed

    Xu, Tongyu; Yang, Qin; Li, Dongpo; Dong, Jinhua; Yu, Zhengkun; Li, Yuxue

    2010-08-01

    FeCl(3)6 H(2)O- and FeBr(3)-catalyzed Prins cyclization/halogenation of alkynyl aldehyde acetals has been realized with acetyl chloride or bromide as halogen source in dichloromethane to afford 2-(1-halobenzylidene or alkylidene)-substituted five-membered carbo- and heterocycles, and thus provides an alternative route for vinylic C-Cl and C-Br bond formation. Five- to eight-membered cyclic enones were efficiently synthesized by FeCl(3)6.H(2)O-catalyzed intramolecular cyclization of alkynyl aldehyde acetals in acetone under mild conditions. An oxocarbonium species generated in situ is proposed to initiate the reaction, and the target products are formed via vinylogous carbenium cation and oxete intermediates according to DFT calculations. Intermolecular reactions of alkynes and aldehyde acetals were also investigated with 20-40 mol% FeCl(3)6.H(2)O catalyst, and produced alpha,beta-unsaturated enones and chlorinated indene derivatives. The present protocol has applications in the synthesis of carbo-, oxa- and azacycles. PMID:20583061

  12. Enzyme-Like Catalysis of the Nazarov Cyclization by Supramolecular Encapsulation

    SciTech Connect

    Hastings, Courtney; Pluth, Michael; Bergman, Robert; Raymond, Kenneth

    2010-03-29

    A primary goal in the design and synthesis of molecular hosts has been the selective recognition and binding of a variety of guests using non-covalent interactions. Supramolecular catalysis, which is the application of such hosts towards catalysis, has much in common with many enzymatic reactions, chiefly the use of both spatially appropriate binding pockets and precisely oriented functional groups to recognize and activate specific substrate molecules. Although there are now many examples which demonstrate how selective encapsulation in a host cavity can enhance the reactivity of a bound guest, all have failed to reach the degree of increased reactivity typical of enzymes. We now report the catalysis of the Nazarov cyclization by a self-assembled coordination cage, a carbon-carbon bond-forming reaction which proceeds under mild, aqueous conditions. The acceleration in this system is over a million-fold, and represents the first example of supramolecular catalysis that achieves the level of rate enhancement comparable to that observed in several enzymes. We explain the unprecedented degree of rate increase as due to the combination of (a) preorganization of the encapsulated substrate molecule, (b) stabilization of the transition state of the cyclization by constrictive binding, and (c) increase in the basicity of the complexed alcohol functionality.

  13. Microenvironmental kinetic effects within a lyotropic smectic biophase model: conformational restrictions in Fischer indole cyclization.

    PubMed

    Ibrahim, H G; Rippie, E G

    1976-11-01

    The microenvironmental orientation effects, arising from an orderer solvent structure, were studied in a model liquid crystalline biophase for the cyclization of a series of 2-substituted cyclohexanone phenylhydrazones. The magnitude of such solvent-induced intramolecular conformational constraints were determined from a comparison of the kinetics of the Fischer indole rearrangement in a lyotropic smectic liquid crystal versus those in an isotropic liquid of similar chemical composition but lacking the structured nature of the mesophase. Solutions consisting of 50% (w/w) polyoxyethylene 6 tridecyl ether or 44% (w/v) polyethylene glycol in aqueous buffers comprised the smectic or isotropic media, respectively. The apparent dissociation constants of the conjugate acids of the phenylhydrazones were determined kinetically, as were their partition coefficients between lipid and polar isotropic phases approximating the compositions of the smectic lamellae. Intrinsic first-order rate constants, corrected for partitioning within the lamellar mesophase, were used to compute the enthalpies and entropies of activation. The somewhat slower intrinsic rates of cyclization and the accompanying less negative entropies of activation generally observed in the liquid crystalline medium, as opposed to the isotropic system, are attributed to the orienting effects of the lamellar lyotropic mesophase.

  14. Dynamic conformations of the CD38-mediated NAD cyclization captured in a single crystal

    PubMed Central

    Zhang, HongMin; Graeff, Richard; Chen, Zhe; Zhang, LiangRen; Zhang, LiHe; Lee, HonCheung; Hao, Quan

    2010-01-01

    The extracellular domain of human CD38 is a multifunctional enzyme involved in the metabolism of two Ca2+ messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). When NAD is used as a substrate, CD38 predominantly hydrolyzes it to ADP-ribose with a trace mount of cADPR produced through cyclization of the substrate. However, a mutation of a key residue at the active site, E146A, inhibits the hydrolysis activity of CD38 but greatly increases its cyclization activity. To understand the role of the residue, E146, in the catalytic process, we determined the crystal structure of the E146A mutant protein with a substrate analogue, ara-2’F-NAD. The structure captured the enzymatic reaction intermediates in six different conformations in a crystallographic asymmetric unit. The structural results indicate a folding-back process for the adenine ring of the substrate and provides the first multiple snap shots of the process. Our approach of utilizing multiple molecules in the crystallographic asymmetric unit should be generally applicable for capturing the dynamic nature of enzymatic catalysis. PMID:21134381

  15. Uganda's National Transmission Backbone Infrastructure Project: Technical Challenges and the Way Forward

    NASA Astrophysics Data System (ADS)

    Bulega, T.; Kyeyune, A.; Onek, P.; Sseguya, R.; Mbabazi, D.; Katwiremu, E.

    2011-10-01

    Several publications have identified technical challenges facing Uganda's National Transmission Backbone Infrastructure project. This research addresses the technical limitations of the National Transmission Backbone Infrastructure project, evaluates the goals of the project, and compares the results against the technical capability of the backbone. The findings of the study indicate a bandwidth deficit, which will be addressed by using dense wave division multiplexing repeaters, leasing bandwidth from private companies. Microwave links for redundancy, a Network Operation Center for operation and maintenance, and deployment of wireless interoperability for microwave access as a last-mile solution are also suggested.

  16. Attosecond Electron Delocalization in the Conduction Band through the Phosphate Backbone of Genomic DNA

    NASA Astrophysics Data System (ADS)

    Ikeura-Sekiguchi, Hiromi; Sekiguchi, Tetsuhiro

    2007-11-01

    Partial density of states in the empty conduction band of the phosphate backbone sites in DNA was probed using energy-dependent resonant Auger spectroscopy. Results show that genomic DNA with periodic backbones exhibits an extended state despite separation of each phosphate group by an insulating sugar group. In antisense DNA with an aperiodic backbone, the equivalent state is localized. Remarkably rapid electron delocalization occurs at ca. 740 attoseconds for wet DNA, as estimated using the core-hole clock method. Such delocalization is comparable to the Fermi velocity of carbon nanotubes.

  17. Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold

    SciTech Connect

    Azoitei, Mihai L.; Correia, Bruno E.; Ban, Yih-En Andrew; Carrico, Chris; Kalyuzhniy, Oleksandr; Chen, Lei; Schroeter, Alexandria; Huang, Po-Ssu; McLellan, Jason S.; Kwong, Peter D.; Baker, David; Strong, Roland K.; Schief, William R.

    2012-02-07

    The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.

  18. Increasing Sequence Diversity with Flexible Backbone Protein Design: The Complete Redesign of a Protein Hydrophobic Core

    SciTech Connect

    Murphy, Grant S.; Mills, Jeffrey L.; Miley, Michael J.; Machius, Mischa; Szyperski, Thomas; Kuhlman, Brian

    2015-10-15

    Protein design tests our understanding of protein stability and structure. Successful design methods should allow the exploration of sequence space not found in nature. However, when redesigning naturally occurring protein structures, most fixed backbone design algorithms return amino acid sequences that share strong sequence identity with wild-type sequences, especially in the protein core. This behavior places a restriction on functional space that can be explored and is not consistent with observations from nature, where sequences of low identity have similar structures. Here, we allow backbone flexibility during design to mutate every position in the core (38 residues) of a four-helix bundle protein. Only small perturbations to the backbone, 12 {angstrom}, were needed to entirely mutate the core. The redesigned protein, DRNN, is exceptionally stable (melting point >140C). An NMR and X-ray crystal structure show that the side chains and backbone were accurately modeled (all-atom RMSD = 1.3 {angstrom}).

  19. Modeling (15)N NMR chemical shift changes in protein backbone with pressure.

    PubMed

    La Penna, Giovanni; Mori, Yoshiharu; Kitahara, Ryo; Akasaka, Kazuyuki; Okamoto, Yuko

    2016-08-28

    Nitrogen chemical shift is a useful parameter for determining the backbone three-dimensional structure of proteins. Empirical models for fast calculation of N chemical shift are improving their reliability, but there are subtle effects that cannot be easily interpreted. Among these, the effects of slight changes in hydrogen bonds, both intramolecular and with water molecules in the solvent, are particularly difficult to predict. On the other hand, these hydrogen bonds are sensitive to changes in protein environment. In this work, the change of N chemical shift with pressure for backbone segments in the protein ubiquitin is correlated with the change in the population of hydrogen bonds involving the backbone amide group. The different extent of interaction of protein backbone with the water molecules in the solvent is put in evidence. PMID:27586953

  20. Modeling 15N NMR chemical shift changes in protein backbone with pressure

    NASA Astrophysics Data System (ADS)

    La Penna, Giovanni; Mori, Yoshiharu; Kitahara, Ryo; Akasaka, Kazuyuki; Okamoto, Yuko

    2016-08-01

    Nitrogen chemical shift is a useful parameter for determining the backbone three-dimensional structure of proteins. Empirical models for fast calculation of N chemical shift are improving their reliability, but there are subtle effects that cannot be easily interpreted. Among these, the effects of slight changes in hydrogen bonds, both intramolecular and with water molecules in the solvent, are particularly difficult to predict. On the other hand, these hydrogen bonds are sensitive to changes in protein environment. In this work, the change of N chemical shift with pressure for backbone segments in the protein ubiquitin is correlated with the change in the population of hydrogen bonds involving the backbone amide group. The different extent of interaction of protein backbone with the water molecules in the solvent is put in evidence.

  1. In a changing environment, network backbone upgrades emerge as a wise investment.

    PubMed

    Cupito, M C

    1997-05-01

    The numbers, locations and needs of users change constantly, but they'll always want more bandwidth. Many experts say that upgrading to higher-speed backbones seems to be the smart investment for unsettled times.

  2. Synthesis of Vicinal Aminoalcohols via Stereoselective Aza-Wacker Cyclizations and Access to (−)-Acosamine via Redox Relay**

    PubMed Central

    Weinstein, Adam B.; Schuman, David P.; Tan, Zhi Xu; Stahl, Shannon S.

    2013-01-01

    Diastereoselective aza-Wacker cyclization of O-allyl hemiaminals under aerobic conditions enables efficient access to 1,2-aminoalcohol derivatives from allylic alcohols. The scope of this method is presented and its utility is highlighted in a streamlined synthesis of the biologically important aminosugar (–)-acosamine. PMID:24105928

  3. Synthetic scope, computational chemistry and mechanism of a base induced 5-endo cyclization of benzyl alkynyl sulfides

    PubMed Central

    Motto, John M.; Castillo, Álvaro; Montemayer, Laura K.; Sheepwash, Erin E.

    2011-01-01

    We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring. Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the formation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium methoxide. Geometries were optimized with CAM-B3LYP/6-311+G(d,p) in acetonitrile with the CPCM solvent model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former. From benzyl(propa-1,2-dien-1-yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base that undergoes 5-endo-trig cyclization followed by a protonation step. PMID:21442022

  4. SYNTHESIS OF TETRAHYDROPYRAN DERIVATIVES VIA A NOVEL INDIUM TRICHLORIDE MEDIATED CROSS-CYCLIZATION BETWEEN EPOXIDES AND HOMOALLYL ALCOHOLS. (R822668)

    EPA Science Inventory

    Abstract

    A cross-cyclization between epoxides and homoallyl alcohols catalyzed by indium chloride generates tetrahydropyran derivatives in high yields.

    Graphical Abstract


    Cyclization and unsaturation rather than isomerisation of side chains govern the selective antibacterial activity of cationic-amphiphilic polymers.

    PubMed

    Uppu, D S S M; Bhowmik, M; Samaddar, S; Haldar, J

    2016-03-28

    Membrane-active agents represent a promising alternative to overcome antibiotic resistance. Here, we report cationic-amphiphilic polymers with variations in the side chain architecture such as cyclization, isomerization and unsaturation that resulted in potent antibacterial activity and low mammalian cell toxicity with a membrane-active mode of action.

  5. Enantioselective Nickel-Catalyzed anti-Carbometallative Cyclizations of Alkynyl Electrophiles Enabled by Reversible Alkenylnickel E/Z Isomerization

    PubMed Central

    2016-01-01

    Nickel-catalyzed additions of arylboronic acids to alkynes, followed by enantioselective cyclizations of the alkenylnickel species onto tethered ketones or enones, are reported. These reactions are reliant upon the formal anti-carbonickelation of the alkyne, which is postulated to occur by the reversible E/Z isomerization of an alkenylnickel species. PMID:27333360

  6. Importance of cytochromes in cyclization reactions: quantum chemical study on a model reaction of proguanil to cycloguanil.

    PubMed

    Arfeen, Minhajul; Patel, Dhilon S; Abbat, Sheenu; Taxak, Nikhil; Bharatam, Prasad V

    2014-10-30

    Proguanil, an anti-malarial prodrug, undergoes cytochrome P450 catalyzed biotransformation to the pharmacologically active triazine metabolite (cycloguanil), which inhibits plasmodial dihydrofolate reductase. This cyclization is catalyzed by CYP2C19 and many anti-malarial lead compounds are being designed and synthesized to exploit this pathway. Quantum chemical calculations were performed using the model species (Cpd I for active species of cytochrome and N4-isopropyl-N6-methylbiguanide for proguanil) to elucidate the mechanism of the cyclization pathway. The overall reaction involves the loss of a water molecule, and is exothermic by approximately 55 kcal/mol, and involves a barrier of approximately 17 kcal/mol. The plausible reaction pathway involves the initial H-radical abstraction from the isopropyl group by Cpd I, followed by two alternative paths- (i) oxygen rebound to provide hydroxyl derivative and (ii) loss of additional H-radical to yield 1,3,5-triazatriene, which undergoes cyclization. This study helped in understanding the role of the active species of cytochromes in this important cyclization reaction.

  7. Pd-Catalyzed C-H activation/oxidative cyclization of acetanilide with norbornene: concise access to functionalized indolines.

    PubMed

    Gao, Yang; Huang, Yubing; Wu, Wanqing; Huang, Kefan; Jiang, Huanfeng

    2014-08-01

    An efficient Pd-catalyzed oxidative cyclization reaction for the synthesis of functionalized indolines by direct C-H activation of acetanilide has been developed. The norbornylpalladium species formed via direct ortho C-H activation of acetanilides is supposed to be a key intermediate in this transformation. PMID:24942255

  8. Mapping membrane protein backbone dynamics: a comparison of site-directed spin labeling with NMR 15N-relaxation measurements.

    PubMed

    Lo, Ryan H; Kroncke, Brett M; Solomon, Tsega L; Columbus, Linda

    2014-10-01

    The ability to detect nanosecond backbone dynamics with site-directed spin labeling (SDSL) in soluble proteins has been well established. However, for membrane proteins, the nitroxide appears to have more interactions with the protein surface, potentially hindering the sensitivity to backbone motions. To determine whether membrane protein backbone dynamics could be mapped with SDSL, a nitroxide was introduced at 55 independent sites in a model polytopic membrane protein, TM0026. Electron paramagnetic resonance spectral parameters were compared with NMR (15)N-relaxation data. Sequential scans revealed backbone dynamics with the same trends observed for the R1 relaxation rate, suggesting that nitroxide dynamics remain coupled to the backbone on membrane proteins.

  9. Does the Mechanism of the Garratt-Braverman Cyclization Differ with Substrates? A Computational Study on Bispropargyl Sulfones, Sulfides, Ethers, Amines, and Methanes.

    PubMed

    Jana, Saibal; Anoop, Anakuthil

    2016-09-01

    We studied the variation in mechanism among different bispropargyl substrates-sulfone, sulfide, ether, amine, and methane-toward Garratt-Braverman (GB) cyclization using density functional theory calculations. Isomerization and cycloaddition are the key steps in the GB cyclization. To compare the reactivity among the various substrates, we computed the free energy of activation (ΔG(⧧)) for the cycloaddition and the cyclization steps, whereas we used the theoretically computed pKa values for the isomerization steps. Our results suggest that the sulfones undergo a relatively fast isomerization followed by slower cyclization, while the ethers undergo a slow isomerization followed by easy cyclization. The methanes and amines are similar to the ethers, and the sulfides showed intermediate behavior. We extended our study to unsymmetrical substrates and compare the results with experiments that suggest the isomerization to be the rate-limiting step for bispropargyl ethers, while cyclization through a diradical intermediate is crucial to the rate for the bispropargyl sulfones. On the basis of these findings, we made predictions on the selectivity of unsymmetrical bispropargyl sulfones, amines, methanes, and sulfides. This is the first detailed mechanistic study on the GB cyclization of bispropargyl substrates other than sulfones. PMID:27464253

  10. Transport properties of a single-molecular diode with one backbone, and two backbones in parallel: Frontier orbital analysis and NEGF-DFT study

    NASA Astrophysics Data System (ADS)

    Zahedi, Ehsan

    2015-05-01

    The conductance and electronic transport properties of a single-molecular diode with one backbone ( 1), and two backbones in parallel ( 2) have been investigated using frontier orbital analysis, and the NEGF formalism combined with DFT. The frontier orbital analysis results demonstrate that the electron transport from one end of the studied molecules to other end is symmetrically allowed and the conductance of the molecule with two parallel backbones is more than the molecule with a single backbone. Transmission spectra study based on the NEGF-DFT of the selected molecules sandwiched between two gold (1 1 1) electrodes showed that, due to a higher coupling between the two electrodes and the molecule 2, the zero-bias conductance is more than twice that of the other molecular junction. Transmission spectra under different biases showed that the maximum constructive interference exists at the bias voltage 0.2, while in some of the biases destructive effects are observed. I- V curves showed that the rectifying directions of molecular junctions 1 and 2 are opposite.

  11. Isothermal Fourier transform infrared microspectrosopic studies on the stability kinetics of solid-state intramolecular cyclization of aspartame sweetener.

    PubMed

    Cheng, Y D; Lin, S Y

    2000-03-01

    A novel Fourier transform infrared (FT-IR) microspectrophotometer equipped with differential scanning calorimetry (DSC) was used to investigate the kinetics of intramolecular cyclization of aspartame (APM) sweetener in the solid state under isothermal conditions. The thermal-dependent changes in the peak intensity of IR spectra at 1543, 1283, and 1259 cm(-1) were examined to explore the reaction. The results support that the intramolecular cyclization process in APM proceeded in three steps: the methoxyl group of ester was first thermolyzed to release methanol, then an acyl cation was attacked by the lone pair of electrons available on nitrogen by an S(N)1 pathway, and finally ring-closure occurred. The intramolecular cyclization of APM determined by this microscopic FT-IR/DSC system was found to follow zero-order kinetics after a brief induction period. The bond cleavage energy (259.38 kJ/mol) of thermolysis for the leaving group of -OCH(3), the bond conversion energy (328.88 kJ/mol) for the amide II NH band to DKP NH band, and the CN bond formation energy (326.93 kJ/mol) of cyclization for the DKP in the APM molecule were also calculated from the Arrhenius equation. The total activation energy of the DKP formation via intramolecular cyclization was 261.33 kJ/mol, calculated by the above summation of the bond energy of cleavage, conversion, and formation, which was near to the value determined by the DSC or TGA method. This indicates that the microscopic FT-IR/DSC system is useful as a potential tool not only to investigate the degradation mechanism of drugs in the solid state but also to directly predict the bond energy of the reaction.

  12. Localized single-stranded bubble mechanism for cyclization of short DNAs

    NASA Astrophysics Data System (ADS)

    Marko, John

    2005-03-01

    Recent experiments (T.E. Cloutier, J. Widom, Mol. Cell 14, 355-62 2004) indicate that double-stranded DNA molecules of approximately 100 base pairs in length have a probability of cyclization which is up to 10^5 times larger than that expected based on the known bending modulus of the double helix. We argue that for short molecules, formation of small (few base pair) regions of single-stranded DNA can provide `flexible hinges' that facilitate loop formation. A statistical-mechanical calculation using a transfer-matrix approach, which treats disordered double helix regions as thermally excited, highly flexible joints, indicates that this mechanism can explain the experimental data. Applications of this type of model and calculation to other situations where localized double helix structural defects may play a important role in DNA higher-order structure will also be discussed. This research was supported by NSF Grant DMR-0203963.

  13. An Ultrasensitive Cyclization-Based Fluorescent Probe for Imaging Native HOBr in Live Cells and Zebrafish.

    PubMed

    Xu, Kehua; Luan, Dongrui; Wang, Xiaoting; Hu, Bo; Liu, Xiaojun; Kong, Fanpeng; Tang, Bo

    2016-10-01

    Bromine has been reported recently as being the 28(th) essential element for human health. HOBr, which is generated in vivo from bromide, is a required factor in the formation of sulfilimine crosslinks in collagen IV. However, to date, no method for the specific detection of native HOBr in vivo has been reported. Herein, we develop a simple small molecular probe for imaging HOBr based on a specific cyclization catalyzed by HOBr. The probe can be easily synthesized in high yield through a Suzuki cross-coupling reaction. The probe exhibits ultrahigh sensitivity at the picomole level, in addition to specificity for HOBr and real-time response. Importantly, without Br(-) stimulation, this probe reports native HOBr levels in HepG2 cells. Thus, the probe is a promising new tool for imaging endogenous HOBr and may provide a means for finding new physiological functions of HOBr in living organisms. PMID:27629766

  14. Asymmetric synthesis of gem-difluoromethylenated linear triquinanes via cascade gem-difluoroalkyl radical cyclization.

    PubMed

    Thaharn, Watcharaporn; Soorukram, Darunee; Kuhakarn, Chutima; Tuchinda, Patoomratana; Pakawatchai, Chaveng; Saithong, Saowanit; Reutrakul, Vichai; Pohmakotr, Manat

    2015-01-16

    An asymmetric synthesis of gem-difluoromethylenated linear triquinanes is described exploiting the synthetic utilities of PhSCF2TMS (5) as a "(•)CF2(-)'' building block. The strategy involves fluoride-catalyzed nucleophilic addition of PhSCF2TMS (5) to chiral ketocyclopentenes 6 to provide silylated adducts 9 or alcohol derivatives 10 and 11. Subsequent cascade radical cyclization of the gem-difluoroalkyl radical generated from silylated adducts 9 or alcohols 10 and 11 afforded gem-difluoromethylenated linear triquinanes 16 as an approximate 1:1 mixture of two diastereomers (16A and 16B). Alternatively, a convenient asymmetric synthesis of gem-difluoromethylenated linear triquinanes 16A can be accomplished by oxidation of 16a (R = H) to provide ketotriquinane 17 followed by a highly stereoselective nucleophilic addition to 17 employing DIBAL, NaBH4, and various Grignard reagents.

  15. Cyclization of 2-acyl- and 2-thioacylaminobenzylcyclopropanes in the gas phase and solution.

    PubMed

    Lebedev, Albert T; Giorgi, Gianluca; Maloshitskaya, Olga A; Kuchumova, Julia; Samgina, Tatiana; Dem'yanov, Piotr; Karakhanova, Nadezhda; Mochalov, Sergey; Fedotov, Alexandr

    2009-01-01

    Mass spectrometry proved itself to be a powerful tool to predict the directions and yields of mono- molecular reactions of organic compounds. Electron ionization (EI) and electrospray ionization (ESI) were used to study possible transformations of N-(ortho-cyclopropylmethylphenyl)arylamides I and N-(ortho- cyclopropylmethylphenyl)arylthioamides II as well as their para-isomers III and IV in a mass spectrometer and to predict directions and yields of their acid catalyzed cyclization reactions. Several five-eight-membered heterocycles were proposed as possible products of intramolecular transformations of compounds I and II. Reactions of compounds I and II in sulfuric acid solutions were carried out and the results obtained were compared with mass spectrometric data. Surprisingly, EI of the studied compounds mimics their solution reactions better than ESI. PMID:19395774

  16. Palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to a library of tetraphenylenes

    NASA Astrophysics Data System (ADS)

    Zhu, Chendan; Zhao, Yue; Wang, Di; Sun, Wei-Yin; Shi, Zhuangzhi

    2016-09-01

    Aryl–aryl bond formation constitutes one of the most important subjects in organic synthesis. The recent developments in direct arylation reactions forming aryl–aryl bond have emerged as very attractive alternatives to traditional cross-coupling reactions. Here, we describe a general palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to build a library of tetraphenylenes. This transformation represents one of the very few examples of C-H activation process that involves simultaneous formation of two aryl–aryl bonds. Oxygen plays a vital role by ensuring high reactivity, with air as the promoter furnished the best results. We anticipate this ligand-free and aerobic catalytic system will simplify the synthesis of tetraphenylenes as many of the reported methods involve use of preformed organometallic reagents and will lead to the discovery of highly efficient new direct arylation process.

  17. Synergistic effects between Lewis and Brønsted acids: application to the Prins cyclization.

    PubMed

    Breugst, Martin; Grée, René; Houk, K N

    2013-10-01

    Brønsted and Lewis acids can catalyze the Prins cyclization, an efficient method for the synthesis of tetrahydropyrans from homoallylic alcohols and carbonyl compounds. Synergistic effects between weak Brønsted and Lewis acids in these reactions have been analyzed by density functional theory [M06-L/def2-QZVP/IEFPCM(CH2Cl2)//M06-L/6-311+G(2df,2p)]. In order to characterize the reactivities of the employed Lewis acids, methyl anion and hydroxide affinities were determined. On the basis of our calculations, we found that the coordination of Lewis acids to carboxylic and sulfonic acids results in a significant increase in the Brønsted acidities of the latter.

  18. Structure of trichodiene synthase from Fusarium sporotrichioides provides mechanistic inferences on the terpene cyclization cascade.

    PubMed

    Rynkiewicz, M J; Cane, D E; Christianson, D W

    2001-11-20

    The x-ray crystal structure of recombinant trichodiene synthase from Fusarium sporotrichioides has been determined to 2.5-A resolution, both unliganded and complexed with inorganic pyrophosphate. This reaction product coordinates to three Mg(2+) ions near the mouth of the active site cleft. A comparison of the liganded and unliganded structures reveals a ligand-induced conformational change that closes the mouth of the active site cleft. Binding of the substrate farnesyl diphosphate similarly may trigger this conformational change, which would facilitate catalysis by protecting reactive carbocationic intermediates in the cyclization cascade. Trichodiene synthase also shares significant structural similarity with other sesquiterpene synthases despite a lack of significant sequence identity. This similarity indicates divergence from a common ancestor early in the evolution of terpene biosynthesis. PMID:11698643

  19. Palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to a library of tetraphenylenes.

    PubMed

    Zhu, Chendan; Zhao, Yue; Wang, Di; Sun, Wei-Yin; Shi, Zhuangzhi

    2016-01-01

    Aryl-aryl bond formation constitutes one of the most important subjects in organic synthesis. The recent developments in direct arylation reactions forming aryl-aryl bond have emerged as very attractive alternatives to traditional cross-coupling reactions. Here, we describe a general palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to build a library of tetraphenylenes. This transformation represents one of the very few examples of C-H activation process that involves simultaneous formation of two aryl-aryl bonds. Oxygen plays a vital role by ensuring high reactivity, with air as the promoter furnished the best results. We anticipate this ligand-free and aerobic catalytic system will simplify the synthesis of tetraphenylenes as many of the reported methods involve use of preformed organometallic reagents and will lead to the discovery of highly efficient new direct arylation process. PMID:27629701

  1. Spectral assignments and structural studies of a warfarin derivative stereoselectively formed by tandem cyclization

    NASA Astrophysics Data System (ADS)

    Velayutham Pillai, M.; Rajeswari, K.; Vidhyasagar, T.

    2015-11-01

    The structural elucidation of a Mannich condensation product of rac-Warfarin with benzaldehyde and methyl amine was carried out using IR, Mass, 1H NMR, 13C NMR, 1H-1H COSY, 1H-13C COSY, DEPT-135, HMBC, NOESY spectra and single crystal X-ray diffraction. Formation of a new pyran ring via a tandem cyclization in the presence of methyl amine was observed. The optimized geometry and HOMO-LUMO energy gap along with other important physical parameters were found by Gaussian 09 program using HF 6-31G (d, p) and B3YLP/DFT 6-31G (d, p) level of theory. The preferred conformation of the piperidine ring in solution state was found to be chair from the NMR spectra. Single crystal X-ray diffraction and optimized geometry (by theoretical study) also confirms the chair conformation in the solid state.

  2. Cyclization of the Monoterpene Citronellal to Isopulegol: A Biomimetic Natural Product Synthesis

    NASA Astrophysics Data System (ADS)

    Jensen, Bruce L.; Malkawi, Ahmed; McGowan, Vanessa

    2000-11-01

    Cyclization of the monoterpene (S)-(--)-citronellal takes place rapidly in the presence of tin(IV) chloride in methylene chloride at 0 °C, affording the cyclic monoterpene isopulegol in a yield of 85%. The experiment reported here mimics the reaction found in the biosynthetic pathway leading to another well-known natural product, menthol. The starting material and final product display easily interpreted infrared and proton-NMR spectra. Coupling patterns and constants produced by the C-3 methine proton establish the all-equatorial substitution pattern of the cyclohexane ring system found in the product. Either a carbocation process or an ene reaction can be used to describe the mechanistic details of this reaction.

  3. Palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to a library of tetraphenylenes

    PubMed Central

    Zhu, Chendan; Zhao, Yue; Wang, Di; Sun, Wei-Yin; Shi, Zhuangzhi

    2016-01-01

    Aryl–aryl bond formation constitutes one of the most important subjects in organic synthesis. The recent developments in direct arylation reactions forming aryl–aryl bond have emerged as very attractive alternatives to traditional cross-coupling reactions. Here, we describe a general palladium-catalyzed direct arylation and cyclization of o-iodobiaryls to build a library of tetraphenylenes. This transformation represents one of the very few examples of C-H activation process that involves simultaneous formation of two aryl–aryl bonds. Oxygen plays a vital role by ensuring high reactivity, with air as the promoter furnished the best results. We anticipate this ligand-free and aerobic catalytic system will simplify the synthesis of tetraphenylenes as many of the reported methods involve use of preformed organometallic reagents and will lead to the discovery of highly efficient new direct arylation process. PMID:27629701

  4. Tuneable enhancement of the salt and thermal stability of polymeric micelles by cyclized amphiphiles

    PubMed Central

    Honda, Satoshi; Yamamoto, Takuya; Tezuka, Yasuyuki

    2013-01-01

    Cyclic molecules provide better stability for their aggregates. Typically in nature, the unique cyclic cell membrane lipids allow thermophilic archaea to inhabit extreme conditions. By mimicking the biological design, the robustness of self-assembled synthetic nanostructures is expected to be improved. Here we report topology effects by cyclized polymeric amphiphiles against their linear counterparts, demonstrating a drastic enhancement in the thermal, as well as salt stability of self-assembled micelles. Furthermore, through coassembly of the linear and cyclic amphiphiles, the stability was successfully tuned for a wide range of temperatures and salt concentrations. The enhanced thermal/salt stability was exploited in a halogen exchange reaction to stimulate the catalytic activity. The mechanism for the enhancement was also investigated. These topology effects by the cyclic amphiphiles offer unprecedented opportunities in polymer materials design unattainable by traditional means. PMID:23481382

  5. Unsaturated syn- and anti-1,2-amino alcohols by cyclization of allylic bis-trichloroacetimidates. stereoselectivity dependence on substrate configuration.

    PubMed

    Grigorjeva, Liene; Kinens, Artis; Jirgensons, Aigars

    2015-01-16

    Disubstituted allylic bis-imidates undergo Lewis acid catalyzed or spontaneous cyclization to oxazolines, which are precursors of unsaturated amino alcohols. Stereoselectivity of the cyclization is mainly determined by the substrate configuration. Highly selective cis-oxazoline formation is achieved starting from anti-E-bis-imidates while trans-oxazoline predominantly forms from anti-Z-bis-imidates. On the basis of DFT calculations, the stereoselectivity trends can be explained by the formation of the energetically most stable carbenium ion conformation, followed by the cyclization via most favorable bond rotations. PMID:25484278

  6. Convergent access to polycyclic cyclopentanoids from α,β-unsaturated acid chlorides and alkynes through a reductive coupling, nazarov cyclization sequence.

    PubMed

    Chaplin, Jason H; Jackson, Kristal; White, Jonathan M; Flynn, Bernard L

    2014-04-18

    Reductive coupling of α,β-unsaturated acid chlorides A with alkynoyls B provides convergent access to Nazarov cyclization precursors, α-carboxy divinyl ketones C. Cyclization of C gives an intermediate oxyallyl cation intermediate D, which can be trapped with tethered arenes (Ar). The resultant products can be further cyclized through nucleophilic displacement of suitable leaving groups X by tethered OH groups to give lactones (in a subsequent step). Where X is a suitable chiral auxiliary (e.g., oxazolidinone) this strategy affords access to homochiral cyclopentanoids. PMID:24697736

  7. Stereoselective Synthesis of Chiral Polycyclic Indolic Architectures through Pd(0) -Catalyzed Tandem Deprotection/Cyclization of Tetrahydro-β-carbolines on Allenes.

    PubMed

    Gobé, Valérian; Guinchard, Xavier

    2015-06-01

    Enantioenriched N-allyl tetrahydro-β-carbolines were prepared by chiral phosphoric acid-catalyzed Pictet-Spengler reactions. The compounds undergo Pd(0) -catalyzed cyclizations through a tandem deprotection/cyclization process. The regioselectivity of the attack is controlled by the chain length and by the substitution pattern of the allene function. Products resulting from 5-exo- or 6-exo-attack were obtained with diastereoisomeric ratio up to 95:5. Azepinopyrrido[3,4-b]indoles were obtained by 7-endo-cyclizations. PMID:25900665

  8. A ruthenium(II) complex as turn-on Cu(II) luminescent sensor based on oxidative cyclization mechanism and its application in vivo

    PubMed Central

    Zhang, Yunfei; Liu, Zonglun; Yang, Kui; Zhang, Yi; Xu, Yongqian; Li, Hongjuan; Wang, Chaoxia; Lu, Aiping; Sun, Shiguo

    2015-01-01

    Copper ions play a vital role in a variety of fundamental physiological processes not only in human beings and plants, but also for extensive insects and microorganisms. In this paper, a novel water-soluble ruthenium(II) complex as a turn-on copper(II) ions luminescent sensor based on o-(phenylazo)aniline was designed and synthesized. The azo group would undergo a specific oxidative cyclization reaction with copper(II) ions and turn into high luminescent benzotriazole, triggering significant luminescent increasements which were linear to the concentrations of copper(II) ions. The sensor distinguished by its high sensitivity (over 80-fold luminescent switch-on response), good selectivity (the changes of the emission intensity in the presence of other metal ions or amino acids were negligible) and low detection limit (4.42 nM) in water. Moreover, the copper(II) luminescent sensor exhibited good photostability under light irradiation. Furthermore, the applicability of the proposed sensor in biological samples assay was also studied and imaged copper(II) ions in living pea aphids successfully. PMID:25640000

  9. A ruthenium(II) complex as turn-on Cu(II) luminescent sensor based on oxidative cyclization mechanism and its application in vivo

    NASA Astrophysics Data System (ADS)

    Zhang, Yunfei; Liu, Zonglun; Yang, Kui; Zhang, Yi; Xu, Yongqian; Li, Hongjuan; Wang, Chaoxia; Lu, Aiping; Sun, Shiguo

    2015-02-01

    Copper ions play a vital role in a variety of fundamental physiological processes not only in human beings and plants, but also for extensive insects and microorganisms. In this paper, a novel water-soluble ruthenium(II) complex as a turn-on copper(II) ions luminescent sensor based on o-(phenylazo)aniline was designed and synthesized. The azo group would undergo a specific oxidative cyclization reaction with copper(II) ions and turn into high luminescent benzotriazole, triggering significant luminescent increasements which were linear to the concentrations of copper(II) ions. The sensor distinguished by its high sensitivity (over 80-fold luminescent switch-on response), good selectivity (the changes of the emission intensity in the presence of other metal ions or amino acids were negligible) and low detection limit (4.42 nM) in water. Moreover, the copper(II) luminescent sensor exhibited good photostability under light irradiation. Furthermore, the applicability of the proposed sensor in biological samples assay was also studied and imaged copper(II) ions in living pea aphids successfully.

  10. One-step synthesis of polysubstituted benzene derivatives by multi-component cyclization of alpha-bromoacetate, malononitrile and aromatic aldehydes.

    PubMed

    Yan, Chao Guo; Song, Xiao Kai; Wang, Qi Fang; Sun, Jing; Siemeling, Ulrich; Bruhn, Clemens

    2008-03-28

    Polysubstituted benzene derivatives with an unprecedented substitution pattern are produced in a novel one-pot multi-component cyclization reaction from pyridine, ethyl alpha-bromoacetate, malononitrile and aromatic aldehyde in refluxing acetonitrile.

  11. A cyclization-induced emission enhancement (CIEE)-based ratiometric fluorogenic and chromogenic probe for the facile detection of a nerve agent simulant DCP.

    PubMed

    Mahapatra, Ajit Kumar; Maiti, Kalipada; Manna, Saikat Kumar; Maji, Rajkishor; Mondal, Sanchita; Das Mukhopadhyay, Chitrangada; Sahoo, Prithidipa; Mandal, Debasish

    2015-06-14

    The first ratiometric fluorescent probe for the detection of a nerve agent simulant was developed based on tandem phosphorylation and intramolecular cyclization, by which high sensitivity as well as large emission shift could be achieved.

  12. Diverse tandem cyclization reactions of o-cyanoanilines and diaryliodonium salts with copper catalyst for the construction of quinazolinimine and acridine scaffolds.

    PubMed

    Pang, Xinlong; Chen, Chao; Su, Xiang; Li, Ming; Wen, Lirong

    2014-12-01

    Two cyclization modes are realized to produce different nitrogen-containing heterocycles, i.e., quinazolin-4(3H)-imines and acridines by assembling o-cyanoanilines and diaryliodonium salts via tandem reaction pathways. PMID:25420123

  13. Domino cyclization-alkylation protocol for the synthesis of 2,3-functionalized indoles from o-alkynylanilines and allylic alcohols.

    PubMed

    Xu, Chang; Murugan, Vinod K; Pullarkat, Sumod A

    2012-05-21

    A practical and efficient protocol for the one-pot synthesis of 2,3-substituted indoles was developed via a palladacycle catalyzed domino cyclization-alkylation reaction involving 2-alkynylanilines and allylic alcohols under mild conditions without any additives.

  14. Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s.

    PubMed

    Wang, Zhiming; Xu, Xingzhu; Gu, Zhanshou; Feng, Wei; Qian, Houjun; Li, Zhengyi; Sun, Xiaoqiang; Kwon, Ohyun

    2016-02-14

    The first Lewis acid-catalyzed intramolecular interrupted Nazarov cyclization of 1,4-pentadien-3-ols is described. Using FeBr3 as the catalyst, a series of new substituted cyclopenta[b]indoles was prepared-through a sequence of Nazarov cyclization, nucleophilic amination, and isomerization-with good yields and high diastereo- and regioselectivities. A similar catalytic process was also developed for the synthesis of structurally interesting spiro[indene-1,4'-quinoline]s. PMID:26771024

  15. Organocatalytic Asymmetric Tandem Nazarov Cyclization/Semipinacol Rearrangement: Rapid Construction of Chiral Spiro[4.4]nonane-1,6-diones.

    PubMed

    Yang, Bin-Miao; Cai, Pei-Jun; Tu, Yong-Qiang; Yu, Zhi-Xiang; Chen, Zhi-Min; Wang, Shuang-Hu; Wang, Shao-Hua; Zhang, Fu-Min

    2015-07-01

    A novel organocatalytic asymmetric tandem Nazarov cyclization/semipinacol rearrangement reaction using "unactivated" substrates has been developed, generating a series of chiral spiro[4.4]nonane-1,6-diones in up to 96% yield and 97% enantiomeric excess. Significantly, it is the first direct example for asymmetric synthesis of cyclopentanones with four stereocenters using Nazarov cyclization. DFT calculations have been applied to understand the reaction mechanism, stereochemistry, and substituent effects. PMID:26076169

  16. Access to Isoquinolines and Isoquinolin-3-ols via Rh(III)-Catalyzed Coupling/Cyclization Cascade Reaction of Arylimidates and Diazo Compounds.

    PubMed

    Li, Xing Guang; Sun, Min; Jin, Qiao; Liu, Kai; Liu, Pei Nian

    2016-05-01

    A Rh(III)-catalyzed coupling/cyclization cascade reaction is described, which involves arylimidates and diazo compounds and proceeds via intermolecular C-C bond formation and subsequent intramolecular C-N bond formation. Mechanistic investigation revealed that the reaction is a two-step process: the initial Rh(III)-catalyzed coupling/cyclization proceeds very fast and the following dehydration is rather slow. The reaction provides a direct approach to isoquinolines and isoquinolin-3-ols without any oxidants. PMID:27042947

  17. Wetting of nonconserved residue-backbones: A feature indicative of aggregation associated regions of proteins.

    PubMed

    Pradhan, Mohan R; Pal, Arumay; Hu, Zhongqiao; Kannan, Srinivasaraghavan; Chee Keong, Kwoh; Lane, David P; Verma, Chandra S

    2016-02-01

    Aggregation is an irreversible form of protein complexation and often toxic to cells. The process entails partial or major unfolding that is largely driven by hydration. We model the role of hydration in aggregation using "Dehydrons." "Dehydrons" are unsatisfied backbone hydrogen bonds in proteins that seek shielding from water molecules by associating with ligands or proteins. We find that the residues at aggregation interfaces have hydrated backbones, and in contrast to other forms of protein-protein interactions, are under less evolutionary pressure to be conserved. Combining evolutionary conservation of residues and extent of backbone hydration allows us to distinguish regions on proteins associated with aggregation (non-conserved dehydron-residues) from other interaction interfaces (conserved dehydron-residues). This novel feature can complement the existing strategies used to investigate protein aggregation/complexation.

  18. Divergent synthesis of chiral heterocycles via sequencing of enantioselective three-component reactions and one-pot subsequent cyclization reactions.

    PubMed

    Tang, Min; Xing, Dong; Huang, Haoxi; Hu, Wenhao

    2015-07-01

    A highly efficient sequencing of catalytic asymmetric three-component reactions of alcohols, diazo compounds and aldimines/aldehydes with one-pot subsequent cyclization reactions was reported. The development of a robust and versatile Rh(ii)/Zr(iv)-BINOL co-catalytic system not only gives high diastereo- and enantioselective controls of the three-component reaction, but also shows excellent functionality tolerances that allow a wide range of functionalities to be pre-installed in each component and readily undergo one-pot subsequent cyclization reactions, thus providing rapid and diversity-oriented synthesis (DOS) of different types of chiral nitrogen- and/or oxygen-containing polyfunctional heterocycles. PMID:25864421

  19. Sequential electrophilic trifluoromethanesulfanylation-cyclization of tryptamine derivatives: synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles.

    PubMed

    Yang, Yi; Jiang, Xueliang; Qing, Feng-Ling

    2012-09-01

    A practical and efficient synthesis of C(3)-trifluoromethanesulfanylated hexahydropyrrolo[2,3-b]indoles 5 from tryptamine derivatives was described. The features of this synthesis included electrophilic activation of C(3) of tryptamine derivatives with "CF(3)S(+)" and cascade ring cyclization by carbamate nucleophile attacking at C(2). Surprisingly, when Lewis acid (BF(3)·OEt(2)) was used as activator instead of proton acid (TsOH·H(2)O) for the electrophilic trifluoromethanesulfanylation of tryptamine derivatives, the uncyclized product 6 was formed preferentially. This sequential trifluoromethanesulfanylation-cyclization protocol was used to synthesize several pyrrolidinoindolinic alkaloid analogues. The cytotoxicity activities of these trifluoromethanesulfanylated alkaloid analogues were evaluated against three cancer cell lines (K562, HeLa, L929). PMID:22889233

  20. SilverCatalyzed Cascade Carboxylation and Cyclization of Trimethyl(2-methylenebut-3-yn-1-yl)silane Derivatives.

    PubMed

    Sekine, Kohei; Sadamitsu, Yuta; Yamada, Tohru

    2015-11-20

    C-C bond-forming carboxylation and cyclization of trimethyl(2-methylenebut-3-yn-1-yl)silane derivatives and carbon dioxide was developed. Silver catalysts and CsF promoted the reaction to afford the corresponding 2-furanone and 2-pyrone derivatives in good-to-high yields. The structure of the 2-furanone was confirmed by single-crystal X-ray crystallography, which revealed that the geometry of the exo-olefin was that of a Z-isomer. When an aromatic ring-substituted alkyne was used, 2-furanone derivatives were selectively obtained via 5-exo-dig cyclization, whereas the reaction of alkyl-substituted alkynes produced 2-pyrone derivatives with high selectivity.

  1. Formation of C(sp2)—Boronate Esters by Borylative Cyclization of Alkynes Using BCl3

    PubMed Central

    Warner, Andrew J.; Lawson, James R.; Fasano, Valerio

    2015-01-01

    Abstract BCl3 is an inexpensive electrophile which induces the borylative cyclization of a wide range of substituted alkynes to regioselectively form polycycles containing synthetically versatile C(sp2)—boronate esters. It proceeds rapidly, with good yields and is compatible with a range of functional groups and substitution patterns. Intermolecular 1,2‐carboboration of alkynes is also achieved using BCl3 to generate trisubstituted vinyl boronate esters. PMID:26237115

  2. Hydroxyl Radical-Mediated Novel Modification of Peptides: N-Terminal Cyclization through the Formation of α-Ketoamide.

    PubMed

    Lee, Seon Hwa; Kyung, Hyunsook; Yokota, Ryo; Goto, Takaaki; Oe, Tomoyuki

    2015-01-20

    The hydroxyl radical-mediated oxidation of peptides and proteins constitutes a large group of post-translational modifications that can result in structural and functional changes. These oxidations can lead to hydroxylation, sulfoxidation, or carbonylation of certain amino acid residues and cleavage of peptide bonds. In addition, hydroxyl radicals can convert the N-terminus of peptides to an α-ketoamide via abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. In the present study, we identified N-terminal cyclization as a novel modification mediated by a hydroxyl radical. The reaction of angiotensin (Ang) II (DRVYIHPF) and the hydroxyl radical generated by the Cu(II)/ascorbic acid (AA) system or UV/hydrogen peroxide system produced N-terminal cyclized-Ang II (Ang C) and pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The structure of Ang C was confirmed by mass spectrometry and comparison to an authentic standard. The subsequent incubation of isolated Ang P in the presence of Cu(II)/AA revealed that Ang P was the direct precursor of Ang C. The proposed mechanism involves the formation of a nitrogen-centered (aminyl) radical, which cyclizes to form a five-membered ring containing the alkoxy radical. The subsequent β-scission reaction of the alkoxyl radical results in the cleavage of the terminal CH3CO group. The initial aminyl radical can be stabilized by chelation to the Cu(II) ions. The affinity of Ang C toward the Ang II type 1 receptor was significantly lower than that of Ang II or Ang P. Ang C was not further metabolized by aminopeptidase A, which converts Ang II to Ang III. Hydroxyl radical-mediated N-terminal cyclization was also observed in other Ang peptides containing N-terminal alanine, arginine, valine, and amyloid β 1-11 (DAEFRHDSGYE).

  3. Reprogramming the Chemodiversity of Terpenoid Cyclization by Remolding the Active Site Contour of epi-Isozizaene Synthase

    PubMed Central

    2015-01-01

    The class I terpenoid cyclase epi-isozizaene synthase (EIZS) utilizes the universal achiral isoprenoid substrate, farnesyl diphosphate, to generate epi-isozizaene as the predominant sesquiterpene cyclization product and at least five minor sesquiterpene products, making EIZS an ideal platform for the exploration of fidelity and promiscuity in a terpenoid cyclization reaction. The hydrophobic active site contour of EIZS serves as a template that enforces a single substrate conformation, and chaperones subsequently formed carbocation intermediates through a well-defined mechanistic sequence. Here, we have used the crystal structure of EIZS as a guide to systematically remold the hydrophobic active site contour in a library of 26 site-specific mutants. Remolded cyclization templates reprogram the reaction cascade not only by reproportioning products generated by the wild-type enzyme but also by generating completely new products of diverse structure. Specifically, we have tripled the overall number of characterized products generated by EIZS. Moreover, we have converted EIZS into six different sesquiterpene synthases: F96A EIZS is an (E)-β-farnesene synthase, F96W EIZS is a zizaene synthase, F95H EIZS is a β-curcumene synthase, F95M EIZS is a β-acoradiene synthase, F198L EIZS is a β-cedrene synthase, and F96V EIZS and W203F EIZS are (Z)-γ-bisabolene synthases. Active site aromatic residues appear to be hot spots for reprogramming the cyclization cascade by manipulating the stability and conformation of critical carbocation intermediates. A majority of mutant enzymes exhibit only relatively modest 2–100-fold losses of catalytic activity, suggesting that residues responsible for triggering substrate ionization readily tolerate mutations deeper in the active site cavity. PMID:24517311

  4. Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions.

    PubMed

    Weinstein, Adam B; Ellman, Jonathan A

    2016-07-01

    The development of Rh(III)-catalyzed C-H conjugate addition/cyclization reactions that provide access to synthetically useful fused bi- and tricyclic nitrogen heterocycles is reported. A broad scope of C-H functionalization substrates and electrophilic olefin coupling partners is effective, and depending on the nature of the directing group, cyclic imide, amide, or heteroaromatic products are obtained. An efficient synthesis of a pyrrolophenanthridine alkaloid natural product, oxoassoanine, highlights the utility of this method.

  5. Rh(III)-Catalyzed C-H Bond Addition/Amine-Mediated Cyclization of Bis-Michael Acceptors.

    PubMed

    Potter, Tyler J; Ellman, Jonathan A

    2016-08-01

    A Rh(III)-catalyzed C-H bond addition/primary amine-promoted cyclization of bis-Michael acceptors is reported. The C-H bond addition step occurs with high chemoselectivity, and the subsequent intramolecular Michael addition, mediated by a primary amine catalyst, sets three contiguous stereocenters with high diastereoselectivity. A broad range of directing groups and both aromatic and alkenyl C-H bonds were shown to be effective in this transformation, affording functionalized piperidines, tetrahydropyrans, and cyclohexanes.

  6. Gold-Catalyzed Intermolecular Ynamide Amination-Initiated Aza-Nazarov Cyclization: Access to Functionalized 2-Aminopyrroles.

    PubMed

    Shu, Chao; Wang, Yong-Heng; Shen, Cang-Hai; Ruan, Peng-Peng; Lu, Xin; Ye, Long-Wu

    2016-07-01

    A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed, allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic rationale for this tandem sequence, especially for the observed high regioselectivity, is also well supported by DFT (density functional theory) computations. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable alternative for the construction of 2-aminopyrroles. PMID:27331406

  7. Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol.

    PubMed

    Tang, Mei-Lin; Peng, Peng; Liu, Zheng-Yu; Zhang, Jian; Yu, Jian-Ming; Sun, Xun

    2016-10-01

    The synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+)-pallidol. PMID:27490335

  8. Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions.

    PubMed

    Weinstein, Adam B; Ellman, Jonathan A

    2016-07-01

    The development of Rh(III)-catalyzed C-H conjugate addition/cyclization reactions that provide access to synthetically useful fused bi- and tricyclic nitrogen heterocycles is reported. A broad scope of C-H functionalization substrates and electrophilic olefin coupling partners is effective, and depending on the nature of the directing group, cyclic imide, amide, or heteroaromatic products are obtained. An efficient synthesis of a pyrrolophenanthridine alkaloid natural product, oxoassoanine, highlights the utility of this method. PMID:27337641

  9. Cerium(IV) ammonium nitrate mediated 5-endo-dig cyclization of α-amino allenylphosphonates to spirodienones.

    PubMed

    Adler, Pauline; Fadel, Antoine; Rabasso, Nicolas

    2015-02-28

    α-Amino allenylphosphonates were treated with cerium(iv) ammonium nitrate under various conditions to form spirodienones in good to excellent yields. The 5-endo-dig cyclization proceeds through the formation of a key iminium intermediate. A comprehensive study on the nature of the solvent used for this reaction was undertaken resulting in the formation of three types of spirodienone scaffolds. PMID:25634577

  10. Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines.

    PubMed

    Sun, Hongnan; Huang, Binbin; Lin, Run; Yang, Chao; Xia, Wujiong

    2015-01-01

    The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring opening followed by cyclization of the resulting haloalkoxy amine. PMID:25977727

  11. Remote Enantioselection Transmitted by an Achiral Peptide Nucleic Acid Backbone

    NASA Technical Reports Server (NTRS)

    Kozlov, Igor A.; Orgel, Leslie E.; Nielsen, Peter E.

    2000-01-01

    short homochiral segment of DNA into a PNA helix could have guaranteed that the next short segment of DNA to be incorporated would have the same handedness as the first. Once two segments of the same handedness were present, the probability that a third segment would have the same handedness would increase, and so on. Evolution could then slowly dilute out the PNA part. This scenario would ultimately allow the formation of a chiral oligonucleotide by processes that are largely resistant to enantiomeric crossinhibition. It is important to note that the ligation of homochiral dinucleotides on a nucleic acid template would probably be at least as enantiospecific as the reaction that we have studied. The disadvantage of using chiral monomers as components of a replicating system arises from the difficulty of generating a first long homochiral template from a racemic mixture of monomers, although results of experiments designed to overcome this difficulty by employing homochiral tetramers have been reported.l l The probability of obtaining a homochiral n-mer from achiral substrates is approximately 1P-I if the nontemplate-directed extension of the primer is not enantioselective. Hence, it would be very hard to get started with a homochiral 40-mer, for example. No such difficulty exists in a scenario that originates with an achiral genetic material and in which the incorporation of very few chiral monomers in this achiral background gradually progresses towards homochirality. It seems possible that some PNA sequences could act as catalysts, analogous to ribozymes, even though PNA lacks clear metal binding sites. Although such catalysts could not be enantioselective, the incorporation of as few as two chiral nucleotides could then impose chiral specificity on the system. Furthermore, such patch chimeras could help to bridge the gap in catalytic potential between PNA and RNA, while guaranteeing enantioselectivity.

  12. Backbone and side-chain resonance assignments of the membrane localization domain from Pasteurella multocida toxin.

    PubMed

    Brothers, Michael C; Geissler, Brett; Hisao, Grant S; Satchell, Karla J F; Wilson, Brenda A; Rienstra, Chad M

    2014-04-01

    (1)H, (13)C, and (15)N chemical shift assignments are presented for the isolated four-helical bundle membrane localization domain (MLD) from Pasteurella multocida toxin (PMT) in its solution state. We have assigned 99% of all backbone and side-chain carbon atoms, including 99% of all backbone residues excluding proline amide nitrogens. Secondary chemical shift analysis using TALOS+ demonstrates four helices, which align with those observed within the MLD in the crystal structure of the C-terminus of PMT (PDB 2EBF) and confirm the use of the available crystal structures as templates for the isolated MLDs.

  13. Electric field induced localization phenomena in a ladder network with superlattice configuration: Effect of backbone environment

    SciTech Connect

    Dutta, Paramita; Karmakar, S. N.; Maiti, Santanu K.

    2014-09-15

    Electric field induced localization properties of a tight-binding ladder network in presence of backbone sites are investigated. Based on Green's function formalism we numerically calculate two-terminal transport together with density of states for different arrangements of atomic sites in the ladder and its backbone. Our results lead to a possibility of getting multiple mobility edges which essentially plays a switching action between a completely opaque to fully or partly conducting region upon the variation of system Fermi energy, and thus, support in fabricating mesoscopic or DNA-based switching devices.

  14. Polyboramines for Hydrogen Release: Polymers Containing Lewis Pairs in their Backbone.

    PubMed

    Ledoux, Audrey; Larini, Paolo; Boisson, Christophe; Monteil, Vincent; Raynaud, Jean; Lacôte, Emmanuel

    2015-12-21

    The one-step polycondensation of diamines and diboranes triggered by the in situ deprotonation of the diammonium salts and concomitant reduction of bisboronic acids leads to the assembly of polymer chains through multiple Lewis pairing in their backbone. These new polyboramines are dihydrogen reservoirs that can be used for the hydrogenation of imines and carbonyl compounds. They also display a unique dihydrogen thermal release profile that is a direct consequence of the insertion of the amine-borane linkages in the polymeric backbone. PMID:26563914

  15. Using Excel To Study The Relation Between Protein Dihedral Angle Omega And Backbone Length

    NASA Astrophysics Data System (ADS)

    Shew, Christopher; Evans, Samari; Tao, Xiuping

    How to involve the uninitiated undergraduate students in computational biophysics research? We made use of Microsoft Excel to carry out calculations of bond lengths, bond angles and dihedral angles of proteins. Specifically, we studied protein backbone dihedral angle omega by examining how its distribution varies with the length of the backbone length. It turns out Excel is a respectable tool for this task. An ordinary current-day desktop or laptop can handle the calculations for midsized proteins in just seconds. Care has to be taken to enter the formulas for the spreadsheet column after column to minimize the computing load. Supported in part by NSF Grant #1238795.

  16. Solvation thermodynamics of amino acid side chains on a short peptide backbone

    SciTech Connect

    Hajari, Timir; Vegt, Nico F. A. van der

    2015-04-14

    The hydration process of side chain analogue molecules differs from that of the actual amino acid side chains in peptides and proteins owing to the effects of the peptide backbone on the aqueous solvent environment. A recent molecular simulation study has provided evidence that all nonpolar side chains, attached to a short peptide backbone, are considerably less hydrophobic than the free side chain analogue molecules. In contrast to this, the hydrophilicity of the polar side chains is hardly affected by the backbone. To analyze the origin of these observations, we here present a molecular simulation study on temperature dependent solvation free energies of nonpolar and polar side chains attached to a short peptide backbone. The estimated solvation entropies and enthalpies of the various amino acid side chains are compared with existing side chain analogue data. The solvation entropies and enthalpies of the polar side chains are negative, but in absolute magnitude smaller compared with the corresponding analogue data. The observed differences are large; however, owing to a nearly perfect enthalpy-entropy compensation, the solvation free energies of polar side chains remain largely unaffected by the peptide backbone. We find that a similar compensation does not apply to the nonpolar side chains; while the backbone greatly reduces the unfavorable solvation entropies, the solvation enthalpies are either more favorable or only marginally affected. This results in a very small unfavorable free energy cost, or even free energy gain, of solvating the nonpolar side chains in strong contrast to solvation of small hydrophobic or nonpolar molecules in bulk water. The solvation free energies of nonpolar side chains have been furthermore decomposed into a repulsive cavity formation contribution and an attractive dispersion free energy contribution. We find that cavity formation next to the peptide backbone is entropically favored over formation of similar sized nonpolar side

  17. Synthesis and properties of a novel molecular beacon containing a benzene-phosphate backbone at its stem moiety.

    PubMed

    Ueno, Yoshihito; Kawamura, Akihiro; Takasu, Keiji; Komatsuzaki, Shinji; Kato, Takumi; Kuboe, Satoru; Kitamura, Yoshiaki; Kitade, Yukio

    2009-07-01

    This paper describes the synthesis and properties of a novel molecular beacon (MB) containing a benzene-phosphate backbone at its stem moiety. The fluorescence intensity of MBs was found to stabilize by the introduction of the benzene-phosphate backbone at its stem moiety. Furthermore, an MB containing the benzene-phosphate backbone was more resistant to DNase I (endonuclease) than an MB comprising natural DNA and 2'-O-methyl-RNA. These results indicate that the MB with the benzene-phosphate backbone is superior as a molecular beacon as compared to the MB composed of natural DNA and 2'-O-methyl-RNA.

  18. Development of novel bifunctional chelating agents containing rigid cyclic hydrocarbon backbones

    SciTech Connect

    Sweet, M.P.; Joshi, V.; Mease, R.C.

    1995-05-01

    We are developing a new class of ligands in which the metal-binding polyaminocarboxylate groups are incorporated onto rigid cyclic hydrocarbon backbones. These ligands, with increased preorganization, should produce radiometal-bioconjugates with higher in-vivo stability. The synthesis of the first in this series of ligands (2,3-diaminobicyclo[2.2.2] octanetetraacetic acid, BODTA) began with a Diels-Alder reaction of 1,3-diacetylimidazolin-2-one and 1,3-cyclohexadiene. Base hydrolysis, alkylation with ethyl iodoacetate, hydrolysis of the esters, and catalytic hydrogenation gave BODTA. For conjugation to MAbs, an average of one COOH group of unsaturated BODTA was converted into an NHS ester using 0.8 equivalent of DCC. The second ligand under development is the decadentate tethered bis-cyclohexyl-EDTA (bis-CDTA) in which 2 cyclohexyl rings are tied together with an ethylene tether. Acylation of monotrityl-1,2-diaminocyclohexane with the di-NHS ester of oxalic acid, reduction of the amide moieties, and removal of the trityl groups followed by cyanomethylation has afforded a hexanitrile whose hydrolysis will produce tethered bis-CDTA. An anti-CEA F(ab{prime}){sub 2} MAb was conjugated with an average of 0.6 BODTA per MAb molecule, labeled with Co-57, and purified by size-exclusion HPLC. Stability of this radioconjugate in mouse serum at 48 h was somewhat better (2% loss) than that of the conventional DTPA-dianhydride (DTPA-DA) conjugate (8% loss). In human tumor-xenografted nude mice (LS-174T cells), tumor (T), blood (B), liver (L), and kidney (K) uptakes (% ID/g) at 24h were: TODTA, 21.6, 4.4, 4.8, 6.0; DTPA-DA, 13.6, 2.5, 5.0, 2.9. The tumor to normal tissue ratios at 48 h for BODTA and DTPA-DA respectively were: T/B, 18.0, 13.9; T/L 4.9, 2.3; T/K, 5.4, 3.9. These preliminary results show promise for using the basic BODTA structure to produce improved bioconjugates with small radiometal ions.

  19. Structural Insights into the Role of the Cyclic Backbone in a Squash Trypsin Inhibitor*

    PubMed Central

    Daly, Norelle L.; Thorstholm, Louise; Greenwood, Kathryn P.; King, Gordon J.; Rosengren, K. Johan; Heras, Begoña; Martin, Jennifer L.; Craik, David J.

    2013-01-01

    MCoTI-II is a head-to-tail cyclic peptide with potent trypsin inhibitory activity and, on the basis of its exceptional proteolytic stability, is a valuable template for the design of novel drug leads. Insights into inhibitor dynamics and interactions with biological targets are critical for drug design studies, particularly for protease targets. Here, we show that the cyclization and active site loops of MCoTI-II are flexible in solution, but when bound to trypsin, the active site loop converges to a single well defined conformation. This finding of reduced flexibility on binding is in contrast to a recent study on the homologous peptide MCoTI-I, which suggested that regions of the peptide are more flexible upon binding to trypsin. We provide a possible explanation for this discrepancy based on degradation of the complex over time. Our study also unexpectedly shows that the cyclization loop, not present in acyclic homologues, facilitates potent trypsin inhibitory activity by engaging in direct binding interactions with trypsin. PMID:24169696

  20. Toward a synthesis of hirsutellone B by the concept of double cyclization

    PubMed Central

    Reber, Keith P.; Tilley, S. David; Carson, Cheryl A.; Sorensen, Erik J.

    2014-01-01

    This account describes a strategy for directly forming three of the six rings found in the polyketide natural product hirsutellone B via a novel cyclization cascade. The key step in our approach comprises two transformations: a large-ring forming, nucleophilic capture of a transient acyl ketene and an intramolecular Diels–Alder reaction, both of which occur in tandem through thermolyses of appropriately functionalized, polyunsaturated dioxinones. These thermally induced “double cyclization” cascades generate three new bonds, four contiguous stereocenters, and a significant fraction of the polycyclic architecture of hirsutellone B. The advanced macrolactam and macrolactone intermediates that were synthesized by this process possess key features of the hirsutellone framework, including the stereochemically dense decahydrofluorene core and the strained para-cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were undermined by competitive O-alkylation reactions. This account also documents how we adapted to this undesired outcome through an evaluation of several distinct strategies for synthesis, as well as our eventual achievement of a formal total synthesis of hirsutellone B. PMID:24032341

  1. Cyclization of polyketides and non-ribosomal peptides on and off their assembly lines.

    PubMed

    Pang, Bo; Wang, Min; Liu, Wen

    2016-02-01

    Modular polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are multifunctional megaenzymes that serve as templates to program the assembly of short carboxylic acids and amino acids in a primarily co-linear manner. The variation, combination, permutation and evolution of their functional units (e.g., modules, domains and proteins) along with their association with external enzymes have resulted in the generation of numerous versions of templates, the roles of which have not been fully recognized in the structural diversification of polyketides, non-ribosomal peptides and their hybrids present in nature. In this Highlight, we focus on the assembly-line enzymology and associated chemistry by providing examples of some newly characterized cyclization reactions that occur on and off the assembly lines during and after chain elongation for the purpose of elucidating the template effects of PKSs and NRPSs. A fundamental understanding of the underlying biosynthetic logic would facilitate the elucidation of chemical information contained within the PKS or NRPS templates and benefit the development of strategies for genome mining, biosynthesis-inspired chemical synthesis and combinatorial biosynthesis. PMID:26604034

  2. Cyclization of ortho-cyclopropylphenyl benzamides in gas and liquid phases.

    PubMed

    Lebedev, A T; Dianova, I V; Mochalov, S S; Lobodin, V V; Samguina, T Y; Gazzaeva, R A

    2001-08-01

    The electron ionization (EI) and collision-induced dissociation (CID) spectra of substituted N-(ortho-cyclopropylphenyl)benzamides 1-7 and N-[ortho-(1-methylcyclopropyl)phenyl]benzamides 8-12 were recorded. In addition to routine bond cleavages, the molecular ions (M+) of 1-12 undergo cyclization into the corresponding 3-aryl-1-alkyl-1-ethyl-1H-benzoxazines and isomeric 5-ethyl-2-oxodibenzoazepines. The presence of a methyl group in the cyclopropyl ring (compounds 8-12) makes the formation of 5-ethyl-2-oxodibenzoazepine less favorable. In accord with mass spectrometric predictions, compound 13 (3-p-tolyl-1-ethyl-1H-benzoxazine) was obtained as a major product of the reaction of N-(ortho-cyclopropylphenyl)-4-methylbenzamide 1 with sulfuric acid. Traces of 5-ethyl-2-oxodibenzoazepine were also detected in gas chromatography-mass spectrometry (GC-MS) analysis of the reaction mixture although the yield was too low to allow its isolation. PMID:11506228

  3. Cyclization of polyketides and non-ribosomal peptides on and off their assembly lines.

    PubMed

    Pang, Bo; Wang, Min; Liu, Wen

    2016-02-01

    Modular polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are multifunctional megaenzymes that serve as templates to program the assembly of short carboxylic acids and amino acids in a primarily co-linear manner. The variation, combination, permutation and evolution of their functional units (e.g., modules, domains and proteins) along with their association with external enzymes have resulted in the generation of numerous versions of templates, the roles of which have not been fully recognized in the structural diversification of polyketides, non-ribosomal peptides and their hybrids present in nature. In this Highlight, we focus on the assembly-line enzymology and associated chemistry by providing examples of some newly characterized cyclization reactions that occur on and off the assembly lines during and after chain elongation for the purpose of elucidating the template effects of PKSs and NRPSs. A fundamental understanding of the underlying biosynthetic logic would facilitate the elucidation of chemical information contained within the PKS or NRPS templates and benefit the development of strategies for genome mining, biosynthesis-inspired chemical synthesis and combinatorial biosynthesis.

  4. Molecular beacon-equilibrium cyclization detection of DNA-protein complexes.

    PubMed

    Vitko, Jason; Rujan, Iulian; Androga, Lagu; Mukerji, Ishita; Bolton, Philip H

    2007-11-01

    Molecular beacon detection of equilibrium cyclization (MBEC) is a novel, high sensitivity technique that can allow DNA-protein complex formation to be studied under diverse conditions in a cost effective and rapid manner that can be adapted to high throughput screening. To demonstrate the ease and utility of applying MBEC to the investigation of the K(D) values of protein-DNA complexes, the sequence-specific Escherichia coli integration host factor (IHF) protein has been used as a test system. Competition between a labeled MBEC DNA construct and unlabeled duplex DNA for IHF binding allows the determination of K(D) values as a function of the DNA duplex sequence. This allows sequence specificity to be monitored while using only a single molecular beacon-labeled DNA. The robustness of MBEC for monitoring protein-DNA complex formation has been further demonstrated by determining the K(D) values as a function of salt concentration to investigate the net number of salt bridges formed in sequence-specific and -nonspecific IHF-DNA complexes. These MBEC results have been compared with those from other approaches.

  5. Conserved elements in the 3' untranslated region of flavivirus RNAs and potential cyclization sequences.

    PubMed

    Hahn, C S; Hahn, Y S; Rice, C M; Lee, E; Dalgarno, L; Strauss, E G; Strauss, J H

    1987-11-01

    We have isolated a cDNA clone after reverse transcription of the genomic RNA of Asibi yellow fever virus whose structure suggests it was formed by self-priming from a 3'-terminal hairpin of 87 nucleotides in the genomic RNA. We have also isolated a clone from cDNA made to Murray Valley encephalitis virus RNA that also appears to have arisen by self-priming from a 3'-terminal structure very similar or identical to that of yellow fever. In addition, 3'-terminal sequencing of the S1 strain of dengue 2 RNA shows that this RNA is also capable of forming a 3'-terminal hairpin of 79 nucleotides. Furthermore, we have identified two 20-nucleotide sequence elements which are present in the 3' untranslated region of all three viruses; one of these sequence elements is repeated in Murray Valley encephalitis and dengue 2 RNA but not in yellow fever RNA. In all three viruses, which represent the three major serological subgroups of the mosquito-borne flaviviruses, the 3'-proximal conserved sequence element, which is found immediately adjacent to the potential 3'-terminal hairpin, is complementary to another conserved domain near the 5' end of the viral RNAs, suggesting that flavivirus RNAs can cyclize (calculated delta G less than -11 kcal; 1 kcal = 4.184 kJ).

  6. The cyclization and polymerization of bacterially expressed proteins using modified self-splicing inteins.

    PubMed

    Evans, T C; Benner, J; Xu, M Q

    1999-06-25

    Mini-inteins derived from Synechocystis sp. (Ssp DnaB intein) and Mycobacterium xenopi (Mxe GyrA intein) that have been modified to cleave peptide bonds at their C and N termini, respectively, were cloned in-frame to the N and C termini of a target protein. Peptide bond cleavage of the modified inteins generated an N-terminal cysteine and a C-terminal thioester on the same protein. These complementary reactive groups underwent intra- or intermolecular condensation to generate circular or polymeric protein species with a new peptide bond at the site of ligation. Three cyclic peptides, BBP, an organ specific localization peptide; RGD, an inhibitor of platelet aggregation; and CDR-H3/C2, which inhibits HIV-1 replication, were isolated using the two-intein system. BBP, RGD, and CDR-H3/C2 had masses of 977.1, 1119.9, and 2098.6 g/mol, respectively, as determined by matrix-assisted laser desorption-time of flight mass spectrometry, which agreed well with the values of 977.2, 1120.3, and 2098.3 g/mol, respectively, predicted for the cyclic species. This system was used to cyclize proteins as large as 395 amino acids. Furthermore, multimers of thioredoxin were formed upon concentration of the reactive species, indicating the potential to form novel biomaterials based on fibrous proteins.

  7. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes.

    PubMed

    Sharp, Kim A; O'Brien, Evan; Kasinath, Vignesh; Wand, A Joshua

    2015-05-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O(2) NH ) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O(2) NH  < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O(2) axis . A calibration curve for backbone entropy vs. O(2) NH is developed, which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O(2) NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, for example, upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O(2) axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements.

  8. Effects of Protein Stabilizing Agents on Thermal Backbone Motions: A Disulfide Trapping Study†

    PubMed Central

    Butler, Scott L.; Falke, Joseph J.

    2010-01-01

    Chemical stabilizers are widely used to enhance protein stability, both in nature and in the laboratory. Here, the molecular mechanism of chemical stabilizers is studied using a disulfide trapping assay to measure the effects of stabilizers on thermal backbone dynamics in the Escherichia coli galactose/glucose binding protein. Two types of backbone fluctuations are examined: (a) relative movements of adjacent surface α-helices within the same domain and (b) interdomain twisting motions. Both types of fluctuations are significantly reduced by all six stabilizers tested (glycerol, sucrose, trehalose, l-glucose, d-glucose, and d-galactose), and in each case larger amplitude motions are inhibited more than smaller ones. Motional inhibition does not require a high-affinity stabilizer binding site, indicating that the effects of stabilizers are nonspecific. Overall, the results support the theory that effective stabilizing agents act by favoring the most compact structure of a protein, thereby reducing local backbone fluctuations away from the fully folded state. Such inhibition of protein backbone dynamics may be a general mechanism of protein stabilization in extreme thermal or chemical environments. PMID:8718847

  9. Animals without Backbones: The Invertebrate Story. Grade Level 5-9.

    ERIC Educational Resources Information Center

    Jerome, Brian; Fuqua, Paul

    This guide, when used in tandem with the videotape "Animals Without Backbones," helps students learn about invertebrates. These materials promote hands-on discovery and learning. The guide is composed of six curriculum-based teaching units: (1) "Getting Started"; (2) "Porifera"; (3) "Cnidarians"; (4) "Worms"; (5) "Mollusks"; (6) "Arthropods"; and…

  10. Graduate Education in Kinesiology: Are We Part of "America's Backbone for Competitiveness and Innovation"?

    ERIC Educational Resources Information Center

    DePauw, Karen P.

    2008-01-01

    Graduate education in the United States has been identified as being the backbone of American competitiveness and innovation in a recent report by the Council of Graduate Schools. The report provides a framework for examining the role of graduate education in partnership with business and government to advance an action agenda for achieving…

  11. On the relationship between NMR-derived amide order parameters and protein backbone entropy changes

    PubMed Central

    Sharp, Kim A.; O’Brien, Evan; Kasinath, Vignesh; Wand, A. Joshua

    2015-01-01

    Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide order parameters (O2NH) are largely determined by the secondary structure and average values appear unrelated to the overall flexibility of the protein. However, analysis of the more flexible subset (O2NH < 0.8) shows that these report both on the local flexibility of the protein and on a different component of the conformational entropy than that reported by the side chain methyl axis order parameters, O2axis. A calibration curve for backbone entropy vs. O2NH is developed which accounts for both correlations between amide group motions of different residues, and correlations between backbone and side chain motions. This calibration curve can be used with experimental values of O2NH changes obtained by NMR relaxation measurements to extract backbone entropy changes, e.g. upon ligand binding. In conjunction with our previous calibration for side chain entropy derived from measured O2axis values this provides a prescription for determination of the total protein conformational entropy changes from NMR relaxation measurements. PMID:25739366

  12. Computer simulation of bottle-brush polymers with flexible backbone: Good solvent versus theta solvent conditions

    NASA Astrophysics Data System (ADS)

    Theodorakis, Panagiotis E.; Hsu, Hsiao-Ping; Paul, Wolfgang; Binder, Kurt

    2011-10-01

    By molecular dynamics simulation of a coarse-grained bead-spring-type model for a cylindrical molecular brush with a backbone chain of Nb effective monomers to which with grafting density σ side chains with N effective monomers are tethered, several characteristic length scales are studied for variable solvent quality. Side chain lengths are in the range 5 ⩽ N ⩽ 40, backbone chain lengths are in the range 50 ⩽ Nb ⩽ 200, and we perform a comparison to results for the bond fluctuation model on the simple cubic lattice (for which much longer chains are accessible, Nb ⩽ 1027, and which corresponds to an athermal, very good, solvent). We obtain linear dimensions of the side chains and the backbone chain and discuss their N-dependence in terms of power laws and the associated effective exponents. We show that even at the theta point the side chains are considerably stretched, their linear dimension depending on the solvent quality only weakly. Effective persistence lengths are extracted both from the orientational correlations and from the backbone end-to-end distance; it is shown that different measures of the persistence length (which would all agree for Gaussian chains) are not mutually consistent with each other and depend distinctly both on Nb and the solvent quality. A brief discussion of pertinent experiments is given.

  13. Side chain chemistry mediates backbone fragmentation in hydrogen deficient peptide radicals.

    PubMed

    Sun, Qingyu; Nelson, Hosea; Ly, Tony; Stoltz, Brian M; Julian, Ryan R

    2009-02-01

    A crown ether based, photolabile radical precursor which forms noncovalent complexes with peptides has been prepared. The peptide/precursor complexes can be electrosprayed, isolated in an ion trap, and then subjected to laser photolysis and collision induced dissociation to generate hydrogen deficient peptide radicals. It is demonstrated that these peptide radicals behave very differently from the hydrogen rich peptide radicals generated by electron capture methods. In fact, it is shown that side chain chemistry dictates both the occurrence and relative abundance of backbone fragments that are observed. Fragmentation at aromatic residues occurs preferentially over most other amino acids. The origin of this selectivity relates to the mechanism by which backbone dissociation is initiated. The first step is abstraction of a beta-hydrogen from the side chain, followed by beta-elimination to yield primarily a-type fragment ions. Calculations reveal that those side chains which can easily lose a beta-hydrogen correlate well with experimentally favored sites for backbone fragmentation. In addition, radical mediated side chain losses from the parent peptide are frequently observed. Eleven amino acids exhibit unique mass losses from side chains which positively identify that particular amino acid as part of the parent peptide. Therefore, side chain losses allow one to unambiguously narrow the possible sequences for a parent peptide, which when combined with predictable backbone fragmentation should lead to greatly increased confidence in peptide identification.

  14. A unified NMR strategy for high-throughput determination of backbone fold of small proteins.

    PubMed

    Kumar, Dinesh; Gautam, Anmol; Hosur, Ramakrishna V

    2012-12-01

    An efficient semi-automated strategy called PFBD (i.e. Protein Fold from Backbone Data only) has been presented for rapid backbone fold determination of small proteins. It makes use of NMR parameters involving backbone atoms only. These include chemical shifts, amide-amide NOEs and H-bonds. The backbone chemical shifts are obtained in an automated manner from the orthogonal 2D projections of variants of HNN and HN(C)N experiments (Kumar et al., in Magn Reson Chem 50(5):357-363, 2012) using AUTOBA (Borkar et al. in J Biomol NMR 50(3):285-297, 2011); backbone H-bonds are manually derived from constant time long-range 2D-HnCO spectrum (Cordier and Grzesiek in J Am Chem Soc 121:1601-1602, 1999); and amide-amide NOEs are derived from 3D HNCO NOESY experiment which provides NOEs along the direct (1)H dimension that has maximum resolution (Lohr and Ruterjans in J Biomol NMR 9(1):371-388, 1997). All the experiments needed for the execution of PFBD can be recorded and analyzed in about 24-48 h depending upon the concentration of the protein and dispersion of amide cross-peaks in the (1)H-(15)N correlation spectrum. Thus, we believe that the strategy, because of its speed and simplicity will be very valuable in Biomolecular NMR community for high-throughput structural proteomics of small folded proteins of MW < 10-12 kDa, the regime where NMR is generally preferred over X-ray crystallography. The strategy has been validated and demonstrated here on two small globular proteins: human ubiquitin (76 aa) and chicken SH3 domain (62 aa). PMID:23054485

  15. Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters.

    PubMed

    Zgarbová, Marie; Luque, F Javier; Sponer, Jiří; Cheatham, Thomas E; Otyepka, Michal; Jurečka, Petr

    2013-05-14

    We present a refinement of the backbone torsion parameters ε and ζ of the Cornell et al. AMBER force field for DNA simulations. The new parameters, denoted as εζOL1, were derived from quantum-mechanical calculations with inclusion of conformation-dependent solvation effects according to the recently reported methodology (J. Chem. Theory Comput. 2012, 7(9), 2886-2902). The performance of the refined parameters was analyzed by means of extended molecular dynamics (MD) simulations for several representative systems. The results showed that the εζOL1 refinement improves the backbone description of B-DNA double helices and G-DNA stem. In B-DNA simulations, we observed an average increase of the helical twist and narrowing of the major groove, thus achieving better agreement with X-ray and solution NMR data. The balance between populations of BI and BII backbone substates was shifted towards the BII state, in better agreement with ensemble-refined solution experimental results. Furthermore, the refined parameters decreased the backbone RMS deviations in B-DNA MD simulations. In the antiparallel guanine quadruplex (G-DNA) the εζOL1 modification improved the description of non-canonical α/γ backbone substates, which were shown to be coupled to the ε/ζ torsion potential. Thus, the refinement is suggested as a possible alternative to the current ε/ζ torsion potential, which may enable more accurate modeling of nucleic acids. However, long-term testing is recommended before its routine application in DNA simulations.

  16. Synthesis and properties of a novel molecular beacon containing a benzene-phosphate backbone at a stem moiety.

    PubMed

    Ueno, Yoshihito; Kawamura, Akihiro; Kato, Takumi; Kitade, Yukio

    2007-01-01

    This paper describes the synthesis and properties of a novel molecular beacon (MB) containing a benzene-phosphate backbone at the stem moieties. Fluorescent intensity of MBs was found to be stabilized by introducing a benzene-phosphate backbone at stem moieties.

  17. Drawing dependent structures, mechanical properties and cyclization behaviors of polyacrylonitrile and polyacrylonitrile/carbon nanotube composite fibers prepared by plasticized spinning.

    PubMed

    Li, Xiang; Qin, Aiwen; Zhao, Xinzhen; Liu, Dapeng; Wang, Haiye; He, Chunju

    2015-09-14

    Drawing to change the structural properties and cyclization behaviors of the polyacrylonitrile (PAN) chains in crystalline and amorphous regions is carried out on PAN and PAN/carbon nanotube (CNT) composite fibers. Various characterization methods including Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and thermal gravimetric analysis are used to monitor the structural evolution and cyclization behaviors of the fibers. With an increase of the draw ratio during the plasticized spinning process, the structural parameters of the fibers, i.e. crystallinity and planar zigzag conformation, are decreased at first, and then increased, which are associated with the heat exchange rate and the oriented-crystallization rate. A possible mechanism for plasticized spinning is proposed to explain the changing trends of crystallinity and planar zigzag conformation. PAN and PAN/CNT fibers exhibit various cyclization behaviors induced by drawing, e.g., the initiation temperature for the cyclization (Ti) of PAN fibers is increased with increasing draw ratio, while Ti of PAN/CNT fibers is decreased. Drawing also facilitates cyclization and lowers the percentage of β-amino nitrile for PAN/CNT fibers during the stabilization.

  18. Drawing dependent structures, mechanical properties and cyclization behaviors of polyacrylonitrile and polyacrylonitrile/carbon nanotube composite fibers prepared by plasticized spinning.

    PubMed

    Li, Xiang; Qin, Aiwen; Zhao, Xinzhen; Liu, Dapeng; Wang, Haiye; He, Chunju

    2015-09-14

    Drawing to change the structural properties and cyclization behaviors of the polyacrylonitrile (PAN) chains in crystalline and amorphous regions is carried out on PAN and PAN/carbon nanotube (CNT) composite fibers. Various characterization methods including Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and thermal gravimetric analysis are used to monitor the structural evolution and cyclization behaviors of the fibers. With an increase of the draw ratio during the plasticized spinning process, the structural parameters of the fibers, i.e. crystallinity and planar zigzag conformation, are decreased at first, and then increased, which are associated with the heat exchange rate and the oriented-crystallization rate. A possible mechanism for plasticized spinning is proposed to explain the changing trends of crystallinity and planar zigzag conformation. PAN and PAN/CNT fibers exhibit various cyclization behaviors induced by drawing, e.g., the initiation temperature for the cyclization (Ti) of PAN fibers is increased with increasing draw ratio, while Ti of PAN/CNT fibers is decreased. Drawing also facilitates cyclization and lowers the percentage of β-amino nitrile for PAN/CNT fibers during the stabilization. PMID:26235219

  19. Backbone chemical shift assignments for Xanthomonas campestris peroxiredoxin Q in the reduced and oxidized states: a dramatic change in backbone dynamics.

    PubMed

    Buchko, Garry W; Perkins, Arden; Parsonage, Derek; Poole, Leslie B; Karplus, P Andrew

    2016-04-01

    Peroxiredoxins (Prx) are ubiquitous enzymes that reduce peroxides as part of antioxidant defenses and redox signaling. While Prx catalytic activity and sensitivity to hyperoxidative inactivation depend on their dynamic properties, there are few examples where their dynamics has been characterized by NMR spectroscopy. Here, we provide a foundation for studies of the solution properties of peroxiredoxin Q from the plant pathogen Xanthomonas campestris (XcPrxQ) by assigning the observable (1)H(N), (15)N, (13)C(α), (13)C(β), and (13)C' chemical shifts for both the reduced (dithiol) and oxidized (disulfide) states. In the reduced state, most of the backbone amide resonances (149/152, 98 %) can be assigned in the XcPrxQ (1)H-(15)N HSQC spectrum. In contrast, a remarkable 51 % (77) of these amide resonances are not visible in the (1)H-(15)N HSQC spectrum of the disulfide state of the enzyme, indicating a substantial change in backbone dynamics associated with the formation of an intramolecular C48-C84 disulfide bond. PMID:26438558

  20. Insights into Diterpene Cyclization from Structure of Bifunctional Abietadiene Synthase from Abies grandis*

    PubMed Central

    Zhou, Ke; Gao, Yang; Hoy, Julie A.; Mann, Francis M.; Honzatko, Richard B.; Peters, Reuben J.

    2012-01-01

    Abietadiene synthase from Abies grandis (AgAS) is a model system for diterpene synthase activity, catalyzing class I (ionization-initiated) and class II (protonation-initiated) cyclization reactions. Reported here is the crystal structure of AgAS at 2.3 Å resolution and molecular dynamics simulations of that structure with and without active site ligands. AgAS has three domains (α, β, and γ). The class I active site is within the C-terminal α domain, and the class II active site is between the N-terminal γ and β domains. The domain organization resembles that of monofunctional diterpene synthases and is consistent with proposed evolutionary origins of terpene synthases. Molecular dynamics simulations were carried out to determine the effect of substrate binding on enzymatic structure. Although such studies of the class I active site do lead to an enclosed substrate-Mg2+ complex similar to that observed in crystal structures of related plant enzymes, it does not enforce a single substrate conformation consistent with the known product stereochemistry. Simulations of the class II active site were more informative, with observation of a well ordered external loop migration. This “loop-in” conformation not only limits solvent access but also greatly increases the number of conformational states accessible to the substrate while destabilizing the nonproductive substrate conformation present in the “loop-out” conformation. Moreover, these conformational changes at the class II active site drive the substrate toward the proposed transition state. Docked substrate complexes were further assessed with regard to the effects of site-directed mutations on class I and II activities. PMID:22219188

  1. Insights into Diterpene Cyclization from Structure of Bifunctional Abietadiene Synthase from Abies grandis

    SciTech Connect

    Zhou, Ke; Gao, Yang; Hoy, Julie A.; Mann, Francis M.; Honzatko, Richard B.; Peters, Reuben J.

    2013-09-24

    Abietadiene synthase from Abies grandis (AgAS) is a model system for diterpene synthase activity, catalyzing class I (ionization-initiated) and class II (protonation-initiated) cyclization reactions. Reported here is the crystal structure of AgAS at 2.3 {angstrom} resolution and molecular dynamics simulations of that structure with and without active site ligands. AgAS has three domains ({alpha}, {beta}, and {gamma}). The class I active site is within the C-terminal {alpha} domain, and the class II active site is between the N-terminal {gamma} and {beta} domains. The domain organization resembles that of monofunctional diterpene synthases and is consistent with proposed evolutionary origins of terpene synthases. Molecular dynamics simulations were carried out to determine the effect of substrate binding on enzymatic structure. Although such studies of the class I active site do lead to an enclosed substrate-Mg{sup 2+} complex similar to that observed in crystal structures of related plant enzymes, it does not enforce a single substrate conformation consistent with the known product stereochemistry. Simulations of the class II active site were more informative, with observation of a well ordered external loop migration. This 'loop-in' conformation not only limits solvent access but also greatly increases the number of conformational states accessible to the substrate while destabilizing the nonproductive substrate conformation present in the 'loop-out' conformation. Moreover, these conformational changes at the class II active site drive the substrate toward the proposed transition state. Docked substrate complexes were further assessed with regard to the effects of site-directed mutations on class I and II activities.

  2. Self-assembly of diphenylalanine backbone homologues and their combination with functionalized carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Dinesh, Bhimareddy; Squillaci, Marco A.; Ménard-Moyon, Cécilia; Samorì, Paolo; Bianco, Alberto

    2015-09-01

    The integration of carbon nanotubes (CNTs) into organized nanostructures is of great interest for applications in materials science and biomedicine. In this work we studied the self-assembly of β and γ homologues of diphenylalanine peptides under different solvent and pH conditions. We aimed to investigate the role of peptide backbone in tuning the formation of different types of nanostructures alone or in combination with carbon nanotubes. In spite of having the same side chain, β and γ peptides formed distinctively different nanofibers, a clear indication of the role played by the backbone homologation on the self-assembly. The variation of the pH allowed to transform the nanofibers into spherical structures. Moreover, the co-assembly of β and γ peptides with carbon nanotubes covalently functionalized with the same peptide generated unique dendritic assemblies. This comparative study on self-assembly using diphenylalanine backbone homologues and of the co-assembly with CNT covalent conjugates is the first example exploring the capacity of β and γ peptides to adopt precise nanostructures, particularly in combination with carbon nanotubes. The dendritic organization obtained by mixing carbon nanotubes and peptides might find interesting applications in tissue engineering and neuronal interfacing.The integration of carbon nanotubes (CNTs) into organized nanostructures is of great interest for applications in materials science and biomedicine. In this work we studied the self-assembly of β and γ homologues of diphenylalanine peptides under different solvent and pH conditions. We aimed to investigate the role of peptide backbone in tuning the formation of different types of nanostructures alone or in combination with carbon nanotubes. In spite of having the same side chain, β and γ peptides formed distinctively different nanofibers, a clear indication of the role played by the backbone homologation on the self-assembly. The variation of the pH allowed to

  3. A transition metal-free tandem process to pyridazinopyrido[3,2-f][1,4]thiazepine-diones via Smiles rearrangement.

    PubMed

    Niu, Xiaoyi; Yang, Bingchuan; Li, Yanqiu; Fang, Shuai; Huang, Zixiao; Xie, Caixia; Ma, Chen

    2013-06-28

    A transition metal-free methodology for the synthesis of pyridazinopyrido[3,2-f][1,4]thiazepine-diones was studied. The construction of this tricyclic system went through a one-pot coupling/Smiles rearrangement/cyclization process. The high yields of pure products were obtained through simple recrystallization.

  4. Direct oxidative coupling of amidine hydrochlorides and methylarenes: TBHP-mediated synthesis of substituted 1,3,5-triazines under metal-free conditions.

    PubMed

    Guo, Wei

    2015-11-01

    Various 2,4,6-trisubstituted 1,3,5-triazines were smoothly formed via TBHP-mediated direct oxidative coupling of amidine and methylarenes. This tandem oxidation-imination-cyclization transformation exhibits a straightforward protocol to prepare 1,3,5-triazines from easily available starting materials and green oxidants under metal-free conditions.

  5. Tris(trimethylsilyl)silane and visible-light irradiation: a new metal- and additive-free photochemical process for the synthesis of indoles and oxindoles.

    PubMed

    da Silva, Gustavo Piva; Ali, Akbar; da Silva, Rodrigo César; Jiang, Hao; Paixão, Márcio W

    2015-10-21

    A combined tris(trimethylsilyl)silane and visible-light-promoted intramolecular reductive cyclization protocol for the synthesis of indoles and oxindoles has been developed. This straightforward and efficient method shows tolerance towards a broad spectrum of functional-groups and enables rapid and practical synthesis of functionalized nitrogen-based heterocycles in high yields under additive and metal-free, mild photochemical conditions.

  6. Asymmetric synthesis of 2,3-dihydropyrroles by ring-opening/cyclization of cyclopropyl ketones using primary amines.

    PubMed

    Xia, Yong; Liu, Xiaohua; Zheng, Haifeng; Lin, Lili; Feng, Xiaoming

    2015-01-01

    The asymmetric ring-opening/cyclization of cyclopropyl ketones with primary amine nucleophiles was catalyzed by a chiral N,N'-dioxide/scandium(III) complex through a kinetic resolution process. A broad range of cyclopropyl ketones and primary amines are suitable substrates of this reaction. The corresponding products were afforded in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield) under mild reaction conditions. This method provides a promising access to chiral 2,3-dihydropyrroles as well as an effective procedure for the kinetic resolution of 2-substituted cyclopropyl ketones.

  7. Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization.

    PubMed

    Wyler, Benjamin; Brucelle, François; Renaud, Philippe

    2016-03-18

    A novel approach to prepare the core structure of Aspidosperma and Strychnos alkaloids is described. The strategy is based on a cyclization cascade involving the formation of quaternary carbon center followed by trapping of the radical intermediate by an aryl azide to build the 5-membered ring of the pyrrolocarbazole system. This reaction is run with triethylborane without the need for any hydrogen atom donor such as a tin hydride or tris(trimethylsilyl)silane, and it furnishes the tetracyclic framework as a single diastereomer. The influence of different N-protecting groups on the starting iodoacetamide has been examined.

  8. Rhodium-Catalyzed Cyclization of 2-Ethynylanilines in the Presence of Isocyanates: Approach toward Indole-3-carboxamides.

    PubMed

    Mizukami, Akiho; Ise, Yumi; Kimachi, Tetsutaro; Inamoto, Kiyofumi

    2016-02-19

    Catalytic synthesis of indole-3-carboxamides from 2-ethynylanilines and isocyanates was achieved in the presence of a rhodium catalyst through a tandem-type, cyclization-addition sequence. This tandem-type process can be performed under mild reaction conditions, affording 2,3-disubstituted indoles in a one-pot manner generally in good to excellent yields. The broad substrate scope and good functional group compatibility make the method highly efficient and widely applicable, providing a facile and entirely novel route toward variously substituted indole-3-carboxamides.

  9. Protecting-Group-Free Total Synthesis of (-)-Lycopodine via Phosphoric Acid Promoted Alkyne Aza-Prins Cyclization.

    PubMed

    Ma, Donghui; Zhong, Zhuliang; Liu, Zaimin; Zhang, Mingjie; Xu, Shiyan; Xu, Dengyu; Song, Dengpeng; Xie, Xingang; She, Xuegong

    2016-09-01

    A protecting-group-free route for the total synthesis of (-)-lycopodine was demonstrated in only 8 steps from Wade's fawcettimine enone (12 steps from commercial availiable (R)-(+)-pulegone). The key core of this alkaloid was constructed through a phosphoric acid promoted and highly stereocontrolled alkyne aza-Prins cyclization reaction, synchronously establishing the bridged B-ring and the C13 quaternary stereocenter. Importantly, the synthesis further features a new efficient approach for the preparation of other lycopodine-type alkaloids. PMID:27529730

  10. Build/couple/pair strategy for the synthesis of stereochemically diverse macrolactams via head-to-tail cyclization.

    PubMed

    Fitzgerald, Mark E; Mulrooney, Carol A; Duvall, Jeremy R; Wei, Jingqiang; Suh, Byung-Chul; Akella, Lakshmi B; Vrcic, Anita; Marcaurelle, Lisa A

    2012-02-13

    A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers of a common linear amine precursor were elaborated to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds were further diversified via capping of two amine functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim of maximizing coverage of chemical space while adhering to a preset range of physicochemical properties.

  11. Enantioselective Construction of Tetrahydroquinolin-5-one-Based Spirooxindole Scaffold via an Organocatalytic Asymmetric Multicomponent [3 + 3] Cyclization.

    PubMed

    Zhu, Qiu-Ning; Zhang, Yu-Chen; Xu, Meng-Meng; Sun, Xiao-Xue; Yang, Xue; Shi, Feng

    2016-09-01

    The first catalytic enantioselective construction of biologically important tetrahydroquinolin-5-one-based spirooxindole has been developed via a chiral cinchona alkaloid catalyzed asymmetric three-component [3 + 3] cyclization of cyclic enaminone, isatin, and malononitrile, which afforded a series of tetrahydroquinolin-5-one-based spirooxindoles in high yields and with excellent enantioselectivities (up to 99% yield, 97:3 er). This reaction could be applicable to large-scale synthesis of enantioenriched tetrahydroquinolin-5-one-based spirooxindoles. This synthetic methodology will not only provide a unique approach for the construction of chiral tetrahydroquinolin-5-one-based spirooxindole scaffolds but also increase our understanding of catalytic enantioselective multicomponent reactions.

  12. Protein backbone and sidechain torsion angles predicted from NMR chemical shifts using artificial neural networks.

    PubMed

    Shen, Yang; Bax, Ad

    2013-07-01

    A new program, TALOS-N, is introduced for predicting protein backbone torsion angles from NMR chemical shifts. The program relies far more extensively on the use of trained artificial neural networks than its predecessor, TALOS+. Validation on an independent set of proteins indicates that backbone torsion angles can be predicted for a larger, ≥90 % fraction of the residues, with an error rate smaller than ca 3.5 %, using an acceptance criterion that is nearly two-fold tighter than that used previously, and a root mean square difference between predicted and crystallographically observed (ϕ, ψ) torsion angles of ca 12º. TALOS-N also reports sidechain χ(1) rotameric states for about 50 % of the residues, and a consistency with reference structures of 89 %. The program includes a neural network trained to identify secondary structure from residue sequence and chemical shifts.

  13. Backbone and side chain chemical shift assignments of apolipophorin III from Galleria mellonella.

    PubMed

    Crowhurst, Karin A; Horn, James V C; Weers, Paul M M

    2016-04-01

    Apolipophorin III, a 163 residue monomeric protein from the greater wax moth Galleria mellonella (abbreviated as apoLp-IIIGM), has roles in upregulating expression of antimicrobial proteins as well as binding and deforming bacterial membranes. Due to its similarity to vertebrate apolipoproteins there is interest in performing atomic resolution analysis of apoLp-IIIGM as part of an effort to better understand its mechanism of action in innate immunity. In the first step towards structural characterization of apoLp-IIIGM, 99 % of backbone and 88 % of side chain (1)H, (13)C and (15)N chemical shifts were assigned. TALOS+ analysis of the backbone resonances has predicted that the protein is composed of five long helices, which is consistent with the reported structures of apolipophorins from other insect species. The next stage in the characterization of apoLp-III from G. mellonella will be to utilize these resonance assignments in solving the solution structure of this protein.

  14. Modifications to the Peptidoglycan Backbone Help Bacteria To Establish Infection ▿

    PubMed Central

    Davis, Kimberly M.; Weiser, Jeffrey N.

    2011-01-01

    Bacterial pathogens that colonize mucosal surfaces have acquired resistance to antimicrobials that are abundant at these sites. One of the main antimicrobials present on mucosal surfaces is lysozyme, a muramidase that hydrolyzes the peptidoglycan backbone of bacteria. Cleavage of the peptidoglycan backbone leads to bacterial cell death and lysis, which releases bacterial fragments, including peptidoglycan, at the site of infection. Peptidoglycan fragments can be recognized by host receptors and initiate an immune response that will aid in clearing infection. Many mucosal pathogens modify the peptidoglycan residues surrounding the cleavage site for lysozyme to avoid peptidoglycan degradation and the release of these proinflammatory fragments. This review will focus specifically on peptidoglycan modifications, their role in lysozyme resistance, and downstream effects on the host immune response to infection. PMID:21041496

  15. Smart-Grid Backbone Network Real-Time Delay Reduction via Integer Programming.

    PubMed

    Pagadrai, Sasikanth; Yilmaz, Muhittin; Valluri, Pratyush

    2016-08-01

    This research investigates an optimal delay-based virtual topology design using integer linear programming (ILP), which is applied to the current backbone networks such as smart-grid real-time communication systems. A network traffic matrix is applied and the corresponding virtual topology problem is solved using the ILP formulations that include a network delay-dependent objective function and lightpath routing, wavelength assignment, wavelength continuity, flow routing, and traffic loss constraints. The proposed optimization approach provides an efficient deterministic integration of intelligent sensing and decision making, and network learning features for superior smart grid operations by adaptively responding the time-varying network traffic data as well as operational constraints to maintain optimal virtual topologies. A representative optical backbone network has been utilized to demonstrate the proposed optimization framework whose simulation results indicate that superior smart-grid network performance can be achieved using commercial networks and integer programming.

  16. Smart-Grid Backbone Network Real-Time Delay Reduction via Integer Programming.

    PubMed

    Pagadrai, Sasikanth; Yilmaz, Muhittin; Valluri, Pratyush

    2016-08-01

    This research investigates an optimal delay-based virtual topology design using integer linear programming (ILP), which is applied to the current backbone networks such as smart-grid real-time communication systems. A network traffic matrix is applied and the corresponding virtual topology problem is solved using the ILP formulations that include a network delay-dependent objective function and lightpath routing, wavelength assignment, wavelength continuity, flow routing, and traffic loss constraints. The proposed optimization approach provides an efficient deterministic integration of intelligent sensing and decision making, and network learning features for superior smart grid operations by adaptively responding the time-varying network traffic data as well as operational constraints to maintain optimal virtual topologies. A representative optical backbone network has been utilized to demonstrate the proposed optimization framework whose simulation results indicate that superior smart-grid network performance can be achieved using commercial networks and integer programming. PMID:25935050

  17. Graft Copolymers with Conducting Polymer Backbones: A Versatile Route to Functional Materials.

    PubMed

    Strover, Lisa T; Malmström, Jenny; Travas-Sejdic, Jadranka

    2016-02-01

    Graft copolymers with a conducting polymer backbone are a promising class of materials for diverse applications including, but not limited to, organic electronics, stimuli-responsive surfaces, sensors, and biomedical devices. These materials take advantage of the unique electrochemical and optoelectronic properties of conducting polymers, complemented by chemical and/or physical properties of the grafted sidechains. In this Personal Account, we discuss our work in designing functional surfaces based on graft copolymers with a conducting polymer backbone, in the context of broader developments in the field. We review the synthetic approaches available for the rational design of conducting-polymer-based graft copolymers, and examine the types of functional surfaces and soluble materials that may be engineered using these techniques.

  18. How Sensitive is the Amide I Vibration of the Polypeptide Backbone to Electric Fields?

    PubMed

    Oh, Kwang-Im; Fiorin, Giacomo; Gai, Feng

    2015-12-01

    Site-selective isotopic labeling of amide carbonyls offers a nonperturbative means to introduce a localized infrared probe into proteins. Although this strategy has been widely used to investigate various biological questions, the dependence of the underlying amide I vibrational frequency on electric fields (or Stark tuning rate) has not been fully determined, which prevents it from being used in a quantitative manner in certain applications. Herein, through the use of experiments and molecular dynamics simulations, the Stark tuning rate of the amide I vibration of an isotopically labeled backbone carbonyl in a transmembrane α-helix is determined to be approximately 1.4 cm(-1) /(MV/cm). This result provides a quantitative basis for using this vibrational model to assess local electric fields in proteins, among other applications. For instance, by using this value, we are able to show that the backbone region of a dipeptide has a surprisingly low dielectric constant.

  19. An experimental teleradiology transmission system using a high-speed ATM backbone network.

    PubMed

    Kato, K; Shimamoto, K; Ishigaki, T; Niimi, R; Ishiguchi, T; Mimura, T; Yamauchi, K; Ikeda, M; Iwata, A

    2000-01-01

    We evaluated the performance of an experimental teleradiology system based on a high-speed ATM backbone network. Image acquisition, transmission and the disk-to-display processing times were measured. Computerized tomography (CT) scans printed on 14 inch x 17 inch (36 cm x 43 cm) films were digitized and transferred over the network. The average time for the entire process was 1 min 30 s. Three radiologists interpreted 20 cases. For CT image interpretation, the reading time for one case ranged from 2 to 12 min (mean 6 min 46 s) on a monitor, and from 1 to 3 min (mean 1 min 31 s) with the original film. The ATM backbone network operating at 156 Mbit/s provided sufficient speed for remote consultation. However, further improvements in the operability of the system, especially the image viewing station, are necessary before it will be satisfactory for clinical use.

  20. Nano-Scale Alignment of Proteins on a Flexible DNA Backbone

    PubMed Central

    Nojima, Tatsuya; Konno, Hiroki; Kodera, Noriyuki; Seio, Kohji; Taguchi, Hideki; Yoshida, Masasuke

    2012-01-01

    Nano-scale alignment of several proteins with freedom of motion is equivalent to an enormous increase in effective local concentration of proteins and will enable otherwise impossible weak and/or cooperative associations between them or with their ligands. For this purpose, a DNA backbone made of six oligodeoxynucleotide (ODN) chains is designed in which five double-stranded segments are connected by four single-stranded flexible linkers. A desired protein with an introduced cysteine is connected covalently to the 5′-end of azido-ODN by catalyst-free click chemistry. Then, six protein-ODN conjugates are assembled with their complementary nucleotide sequences into a single multi-protein-DNA complex, and six proteins are aligned along the DNA backbone. Flexible alignment of proteins is directly observed by high-speed AFM imaging, and association of proteins with weak interaction is demonstrated by fluorescence resonance energy transfer between aligned proteins. PMID:23300700

  1. Protein backbone torsion angle-based structure comparison and secondary structure database web server.

    PubMed

    Jung, Sunghoon; Bae, Se-Eun; Ahn, Insung; Son, Hyeon S

    2013-09-01

    Structural information has been a major concern for biological and pharmaceutical studies for its intimate relationship to the function of a protein. Three-dimensional representation of the positions of protein atoms is utilized among many structural information repositories that have been published. The reliability of the torsional system, which represents the native processes of structural change in the structural analysis, was partially proven with previous structural alignment studies. Here, a web server providing structural information and analysis based on the backbone torsional representation of a protein structure is newly introduced. The web server offers functions of secondary structure database search, secondary structure calculation, and pair-wise protein structure comparison, based on a backbone torsion angle representation system. Application of the implementation in pair-wise structural alignment showed highly accurate results. The information derived from this web server might be further utilized in the field of ab initio protein structure modeling or protein homology-related analyses.

  2. Solid polymer battery electrolyte and reactive metal-water battery

    DOEpatents

    Harrup, Mason K.; Peterson, Eric S.; Stewart, Frederick F.

    2000-01-01

    In one implementation, a reactive metal-water battery includes an anode comprising a metal in atomic or alloy form selected from the group consisting of periodic table Group 1A metals, periodic table Group 2A metals and mixtures thereof. The battery includes a cathode comprising water. Such also includes a solid polymer electrolyte comprising a polyphosphazene comprising ligands bonded with a phosphazene polymer backbone. The ligands comprise an aromatic ring containing hydrophobic portion and a metal ion carrier portion. The metal ion carrier portion is bonded at one location with the polymer backbone and at another location with the aromatic ring containing hydrophobic portion. The invention also contemplates such solid polymer electrolytes use in reactive metal/water batteries, and in any other battery.

  3. Solving the puzzling competition of the thermal C2–C6 vs Myers–Saito cyclization of enyne-carbodiimides

    PubMed Central

    Rana, Anup; Cinar, Mehmet Emin; Samanta, Debabrata

    2016-01-01

    Summary The mechanism of the thermal cyclization of enyne-carbodiimides 7a–c has been studied computationally by applying the DFT method. The results indicate that enyne-carbodiimides preferentially follow the C2–C6 (Schmittel) cyclization pathway in a concerted fashion although the Myers–Saito diradical formation is kinetically preferred. The experimentally verified preference of the C2–C6 over the Myers–Saito pathway is guided by the inability of the Myers–Saito diradical to kinetically compete in the rate-determining trapping reactions, either inter- or intramolecular, with the concerted C2–C6 cyclization. As demonstrated with enyne-carbodiimide 11, the Myers–Saito channel can be made the preferred pathway if the trapping reaction by hydrogen transfer is no more rate determining. PMID:26877807

  4. A polarizable force field for computing the infrared spectra of the polypeptide backbone.

    PubMed

    Schultheis, Verena; Reichold, Rudolf; Schropp, Bernhard; Tavan, Paul

    2008-10-01

    The shapes of the amide bands in the infrared (IR) spectra of proteins and peptides are caused by electrostatically coupled vibrations within the polypeptide backbone and code the structures of these biopolymers. A structural decoding of the amide bands has to resort to simplified models because the huge size of these macromolecules prevents the application of accurate quantum mechanical methods such as density functional theory (DFT). Previous models employed transition-dipole coupling methods that are of limited accuracy. Here we propose a concept for the computation of protein IR spectra, which describes the molecular mechanics (MM) of polypeptide backbones by a polarizable force field of "type II". By extending the concepts of conventional polarizable MM force fields, such a PMM/II approach employs field-dependent parameters not only for the electrostatic signatures of the molecular components but also for the local potentials modeling the stiffness of chemical bonds with respect to elongations, angle deformations, and torsions. Using a PMM/II force field, the IR spectra of the polypeptide backbone can be efficiently calculated from the time dependence of the backbone's dipole moment during a short (e.g., 100 ps) MD simulation by Fourier transformation. PMM/II parameters are derived for harmonic bonding potentials of amide groups in polypeptides from a series of DFT calculations on the model molecule N-methylacetamide (NMA) exposed to homogeneous external electric fields. The amide force constants are shown to vary by as much as 20% for relevant field strengths. As a proof of principle, it is shown that the large solvatochromic effects observed in the IR spectra of NMA upon transfer from the gas phase into aqueous solution are not only excellently reproduced by DFT/MM simulations but are also nicely modeled by the PMM/II approach. The tasks remaining for a proof of practice are specified.

  5. Tritium containing polymers having a polymer backbone substantially void of tritium

    DOEpatents

    Jensen, George A.; Nelson, David A.; Molton, Peter M.

    1992-01-01

    A radioluminescent light source comprises a solid mixture of a phosphorescent substance and a tritiated polymer. The solid mixture forms a solid mass having length, width, and thickness dimensions, and is capable of self-support. In one aspect of the invention, the phosphorescent substance comprises solid phosphor particles supported or surrounded within a solid matrix by a tritium containing polymer. The tritium containing polymer comprises a polymer backbone which is essentially void of tritium.

  6. Tritium containing polymers having a polymer backbone substantially void of tritium

    DOEpatents

    Jensen, G.A.; Nelson, D.A.; Molton, P.M.

    1992-03-31

    A radioluminescent light source comprises a solid mixture of a phosphorescent substance and a tritiated polymer. The solid mixture forms a solid mass having length, width, and thickness dimensions, and is capable of self-support. In one aspect of the invention, the phosphorescent substance comprises solid phosphor particles supported or surrounded within a solid matrix by a tritium containing polymer. The tritium containing polymer comprises a polymer backbone which is essentially void of tritium. 2 figs.

  7. On the satisfaction of backbone-carbonyl lone pairs of electrons in protein structures.

    PubMed

    Bartlett, Gail J; Woolfson, Derek N

    2016-04-01

    Protein structures are stabilized by a variety of noncovalent interactions (NCIs), including the hydrophobic effect, hydrogen bonds, electrostatic forces and van der Waals' interactions. Our knowledge of the contributions of NCIs, and the interplay between them remains incomplete. This has implications for computational modeling of NCIs, and our ability to understand and predict protein structure, stability, and function. One consideration is the satisfaction of the full potential for NCIs made by backbone atoms. Most commonly, backbone-carbonyl oxygen atoms located within α-helices and β-sheets are depicted as making a single hydrogen bond. However, there are two lone pairs of electrons to be satisfied for each of these atoms. To explore this, we used operational geometric definitions to generate an inventory of NCIs for backbone-carbonyl oxygen atoms from a set of high-resolution protein structures and associated molecular-dynamics simulations in water. We included more-recently appreciated, but weaker NCIs in our analysis, such as n→π* interactions, Cα-H bonds and methyl-H bonds. The data demonstrate balanced, dynamic systems for all proteins, with most backbone-carbonyl oxygen atoms being satisfied by two NCIs most of the time. Combinations of NCIs made may correlate with secondary structure type, though in subtly different ways from traditional models of α- and β-structure. In addition, we find examples of under- and over-satisfied carbonyl-oxygen atoms, and we identify both sequence-dependent and sequence-independent secondary-structural motifs in which these reside. Our analysis provides a more-detailed understanding of these contributors to protein structure and stability, which will be of use in protein modeling, engineering and design. PMID:26833776

  8. On the satisfaction of backbone-carbonyl lone pairs of electrons in protein structures.

    PubMed

    Bartlett, Gail J; Woolfson, Derek N

    2016-04-01

    Protein structures are stabilized by a variety of noncovalent interactions (NCIs), including the hydrophobic effect, hydrogen bonds, electrostatic forces and van der Waals' interactions. Our knowledge of the contributions of NCIs, and the interplay between them remains incomplete. This has implications for computational modeling of NCIs, and our ability to understand and predict protein structure, stability, and function. One consideration is the satisfaction of the full potential for NCIs made by backbone atoms. Most commonly, backbone-carbonyl oxygen atoms located within α-helices and β-sheets are depicted as making a single hydrogen bond. However, there are two lone pairs of electrons to be satisfied for each of these atoms. To explore this, we used operational geometric definitions to generate an inventory of NCIs for backbone-carbonyl oxygen atoms from a set of high-resolution protein structures and associated molecular-dynamics simulations in water. We included more-recently appreciated, but weaker NCIs in our analysis, such as n→π* interactions, Cα-H bonds and methyl-H bonds. The data demonstrate balanced, dynamic systems for all proteins, with most backbone-carbonyl oxygen atoms being satisfied by two NCIs most of the time. Combinations of NCIs made may correlate with secondary structure type, though in subtly different ways from traditional models of α- and β-structure. In addition, we find examples of under- and over-satisfied carbonyl-oxygen atoms, and we identify both sequence-dependent and sequence-independent secondary-structural motifs in which these reside. Our analysis provides a more-detailed understanding of these contributors to protein structure and stability, which will be of use in protein modeling, engineering and design.

  9. The Role of Methoxy Group in the Nazarov Cyclization of 1,5- bis-(2-Methoxyphenyl)-1,4-Pentadien-3-one in the Gas Phase and Condensed Phase

    NASA Astrophysics Data System (ADS)

    Cyriac, June; Paulose, Justin; George, Mathai; Ramesh, Marupaka; Srinivas, Ragampeta; Giblin, Daryl; Gross, Michael L.

    2014-03-01

    ESI-protonated 1,5- bis-(2-methoxyphenyl)-1,4-pentadien-3-one (1) undergoes a gas-phase Nazarov cyclization and dissociates via expulsions of ketene and anisole. The dissociations of the [M + D]+ ions are accompanied by limited HD scrambling that supports the proposed cyclization. Solution cyclization of 1 was effected to yield the cyclic ketone, 2,3- bis-(2-methoxyphenyl)-cyclopent-2-ene-1-one, (2) on a time scale that is significantly shorter than the time for cyclization of dibenzalacetone. The dissociation characteristics of the ESI-generated [M + H]+ ion of the synthetic cyclic ketone closely resemble those of 1, suggesting that gas-phase and solution cyclization products are the same. Additional mechanistic studies by density functional theory (DFT) methods of the gas-phase reaction reveals that the initial cyclization is followed by two sequential 1,2-aryl migrations that account for the observed structure of the cyclic product in the gas phase and solution. Furthermore, the DFT calculations show that the methoxy group serves as a catalyst for the proton migrations necessary for both cyclization and fragmentation after aryl migration. An isomer formed by moving the 2-methoxy to the 4-position requires relatively higher collision energy for the elimination of anisole, as is consistent with DFT calculations. Replacement of the 2-methoxy group with an OH shows that the cyclization followed by aryl migration and elimination of phenol occurs from the [M + H]+ ion at low energy similar to that for 1.

  10. Self-assembly of diphenylalanine backbone homologues and their combination with functionalized carbon nanotubes.

    PubMed

    Dinesh, Bhimareddy; Squillaci, Marco A; Ménard-Moyon, Cécilia; Samorì, Paolo; Bianco, Alberto

    2015-10-14

    The integration of carbon nanotubes (CNTs) into organized nanostructures is of great interest for applications in materials science and biomedicine. In this work we studied the self-assembly of β and γ homologues of diphenylalanine peptides under different solvent and pH conditions. We aimed to investigate the role of peptide backbone in tuning the formation of different types of nanostructures alone or in combination with carbon nanotubes. In spite of having the same side chain, β and γ peptides formed distinctively different nanofibers, a clear indication of the role played by the backbone homologation on the self-assembly. The variation of the pH allowed to transform the nanofibers into spherical structures. Moreover, the co-assembly of β and γ peptides with carbon nanotubes covalently functionalized with the same peptide generated unique dendritic assemblies. This comparative study on self-assembly using diphenylalanine backbone homologues and of the co-assembly with CNT covalent conjugates is the first example exploring the capacity of β and γ peptides to adopt precise nanostructures, particularly in combination with carbon nanotubes. The dendritic organization obtained by mixing carbon nanotubes and peptides might find interesting applications in tissue engineering and neuronal interfacing.

  11. Repacking protein cores with backbone freedom: structure prediction for coiled coils.

    PubMed

    Harbury, P B; Tidor, B; Kim, P S

    1995-08-29

    Progress in homology modeling and protein design has generated considerable interest in methods for predicting side-chain packing in the hydrophobic cores of proteins. Present techniques are not practically useful, however, because they are unable to model protein main-chain flexibility. Parameterization of backbone motions may represent a general and efficient method to incorporate backbone relaxation into such fixed main-chain models. To test this notion, we introduce a method for treating explicitly the backbone motions of alpha-helical bundles based on an algebraic parameterization proposed by Francis Crick in 1953 [Crick, F. H. C. (1953) Acta Crystallogr. 6, 685-689]. Given only the core amino acid sequence, a simple calculation can rapidly reproduce the crystallographic main-chain and core side-chain structures of three coiled coils (one dimer, one trimer, and one tetramer) to within 0.6-A root-mean-square deviations. The speed of the predictive method [approximately 3 min per rotamer choice on a Silicon Graphics (Mountain View, CA) 4D/35 computer] permits it to be used as a design tool.

  12. Temperature dependence of fast carbonyl backbone dynamics in chicken villin headpiece subdomain.

    PubMed

    Vugmeyster, Liliya; Ostrovsky, Dmitry

    2011-06-01

    Temperature-dependence of protein dynamics can provide information on details of the free energy landscape by probing the characteristics of the potential responsible for the fluctuations. We have investigated the temperature-dependence of picosecond to nanosecond backbone dynamics at carbonyl carbon sites in chicken villin headpiece subdomain protein using a combination of three NMR relaxation rates: (13)C' longitudinal rate, and two cross-correlated rates involving dipolar and chemical shift anisotropy (CSA) relaxation mechanisms, (13)C'/(13)C'-(13)C(α) CSA/dipolar and (13)C'/(13)C'-(15)N CSA/dipolar. Order parameters have been extracted using the Lipari-Szabo model-free approach assuming a separation of the time scales of internal and molecular motions in the 2-16°C temperature range. There is a gradual deviation from this assumption from lower to higher temperatures, such that above 16°C the separation of the time scales is inconsistent with the experimental data and, thus, the Lipari-Szabo formalism can not be applied. While there are variations among the residues, on the average the order parameters indicate a markedly steeper temperature dependence at backbone carbonyl carbons compared to that probed at amide nitrogens in an earlier study. This strongly advocates for probing sites other than amide nitrogen for accurate characterization of the potential and other thermodynamics characteristics of protein backbone.

  13. Protein backbone angle restraints from searching a database for chemical shift and sequence homology.

    PubMed

    Cornilescu, G; Delaglio, F; Bax, A

    1999-03-01

    Chemical shifts of backbone atoms in proteins are exquisitely sensitive to local conformation, and homologous proteins show quite similar patterns of secondary chemical shifts. The inverse of this relation is used to search a database for triplets of adjacent residues with secondary chemical shifts and sequence similarity which provide the best match to the query triplet of interest. The database contains 13C alpha, 13C beta, 13C', 1H alpha and 15N chemical shifts for 20 proteins for which a high resolution X-ray structure is available. The computer program TALOS was developed to search this database for strings of residues with chemical shift and residue type homology. The relative importance of the weighting factors attached to the secondary chemical shifts of the five types of resonances relative to that of sequence similarity was optimized empirically. TALOS yields the 10 triplets which have the closest similarity in secondary chemical shift and amino acid sequence to those of the query sequence. If the central residues in these 10 triplets exhibit similar phi and psi backbone angles, their averages can reliably be used as angular restraints for the protein whose structure is being studied. Tests carried out for proteins of known structure indicate that the root-mean-square difference (rmsd) between the output of TALOS and the X-ray derived backbone angles is about 15 degrees. Approximately 3% of the predictions made by TALOS are found to be in error.

  14. Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity.

    PubMed

    Trevino, Simon G; Zhang, Na; Elenko, Mark P; Lupták, Andrej; Szostak, Jack W

    2011-08-16

    Multiple lines of evidence support the hypothesis that the early evolution of life was dominated by RNA, which can both transfer information from generation to generation through replication directed by base-pairing, and carry out biochemical activities by folding into functional structures. To understand how life emerged from prebiotic chemistry we must therefore explain the steps that led to the emergence of the RNA world, and in particular, the synthesis of RNA. The generation of pools of highly pure ribonucleotides on the early Earth seems unlikely, but the presence of alternative nucleotides would support the assembly of nucleic acid polymers containing nonheritable backbone heterogeneity. We suggest that homogeneous monomers might not have been necessary if populations of heterogeneous nucleic acid molecules could evolve reproducible function. For such evolution to be possible, function would have to be maintained despite the repeated scrambling of backbone chemistry from generation to generation. We have tested this possibility in a simplified model system, by using a T7 RNA polymerase variant capable of transcribing nucleic acids that contain an approximately 11 mixture of deoxy- and ribonucleotides. We readily isolated nucleotide-binding aptamers by utilizing an in vitro selection process that shuffles the order of deoxy- and ribonucleotides in each round. We describe two such RNA/DNA mosaic nucleic acid aptamers that specifically bind ATP and GTP, respectively. We conclude that nonheritable variations in nucleic acid backbone structure may not have posed an insurmountable barrier to the emergence of functionality in early nucleic acids.

  15. East vergent structure of Backbone Range: Insights from A-Lan-Yi area and sandbox modeling

    NASA Astrophysics Data System (ADS)

    Lee, C. A.; Lu, C. Y.

    2015-12-01

    Southern Taiwan, including Pingtung peninsula and Taitung, is the incipient oblique collision zone of Eurasian plate and Philippine Sea plate. The Luzon volcanic arc converged toward Taiwan Island and formed Hengchun Ridge south offshore Taiwan. Thus, Taiwan mountain belt developed from north to south as the Backbone Range, so that we can infer the incipient feature structure from the topography and outcrop study of southern Taiwan. Our field survey of this study concentrated at the southeast coastline of Taiwan, also known as A-Lan-Yi Trail. According to previous study, the deformational structures such as faults and folds are consistent with regional kinematic processes, and the preserved transpression structure is the most important evidence of incipient collision. In this study, we use the sedimentary sequences of study area to trace the regional tectonics from north to south. Discovered structures in this area show the similar kinematic history as the eastern flank of Backbone Range, so that we suggest they are at the same series of a tectonic event. To complete the regional structure mapping in this accessible area, besides the field geological data, we also applied the LiDAR-derived DTM which is a 3D visualization technology to improve our topography information. In addition, we use the sandbox modeling to demonstrate the development of structures in the eastern flank of Backbone Range. After combining the results of field observation and regional structure mapping, this study provides a strong evidence of backthrusting and backfolding deformation during the incipient oblique collision stage.

  16. Probing the Backbone Function of Tumor Targeting Peptides by an Amide-to-Triazole Substitution Strategy.

    PubMed

    Valverde, Ibai E; Vomstein, Sandra; Fischer, Christiane A; Mascarin, Alba; Mindt, Thomas L

    2015-09-24

    Novel backbone-modified radiolabeled analogs based on the tumor targeting peptide bombesin were synthesized and fully evaluated in vitro and in vivo. We have recently introduced the use of 1,4-disubstituted 1,2,3-triazoles as metabolically stable trans-amide bond surrogates in radiolabeled peptides in order to improve their tumor targeting. As an extension of our approach, we now report several backbone-modified analogs of the studied bombesin peptide bearing multiple triazole substitutions. We investigated the effect of the modifications on several biological parameters including the internalization of the radiopeptidomimetics into tumor cells, their affinity toward the gastrin releasing peptide receptor (GRPr), metabolic stability in blood plasma, and biodistribution in mice bearing GRPr-expressing xenografts. The backbone-modified radiotracers exhibited a significantly increased resistance to proteolytic degradation. In addition, some of the radiopeptidomimetics retained a nanomolar affinity toward GRPr, resulting in an up to 2-fold increased tumor uptake in vivo in comparison to a (all amide bond) reference compound. PMID:26309061

  17. A practical implementation of cross-spectrum in protein backbone resonance assignment.

    PubMed

    Chen, Kang; Delaglio, Frank; Tjandra, Nico

    2010-04-01

    The concept of cross-spectrum is applied in protein NMR spectroscopy to assist in the backbone sequential resonance assignment. Cross-spectrum analysis is used routinely to reveal correlations in frequency domains as a means to reveal common features contained in multiple time series. Here the cross-spectrum between related NMR spectra, for example HNCO and HN(CA)CO, can be calculated with point-by-point multiplications along their common C' carbon axis. In the resulting higher order cross-spectrum, an enhanced correlation signal occurs at every common i-1 carbon frequency allowing the amide proton H(N) (and nitrogen N) resonances from residues i and i-1 to be identified. The cross-spectrum approach is demonstrated using 2D spectra H(N)CO, H(NCA)CO, H(NCO)CACB, and H(N)CACB measured on a 15N/13C double-labeled Ubiquitin sample. These 2D spectra are used to calculate two pseudo-3D cross-spectra, H(i)-H(i)(-1)-C'(i)(-1) and H(i)-H(i)(-1)-CA(i)(-1)CB(i)(-1). We show using this approach, backbone resonances of H, C', CA, and CB can be fully assigned without ambiguity. The cross-spectrum principle is expected to offer an easy, practical, and more quantitative approach for heteronuclear backbone resonance assignment. PMID:20053573

  18. RASP: rapid and robust backbone chemical shift assignments from protein structure.

    PubMed

    MacRaild, Christopher A; Norton, Raymond S

    2014-03-01

    Chemical shift prediction has an unappreciated power to guide backbone resonance assignment in cases where protein structure is known. Here we describe Resonance Assignment by chemical Shift Prediction (RASP), a method that exploits this power to derive protein backbone resonance assignments from chemical shift predictions. Robust assignments can be obtained from a minimal set of only the most sensitive triple-resonance experiments, even for spectroscopically challenging proteins. Over a test set of 154 proteins RASP assigns 88 % of residues with an accuracy of 99.7 %, using only information available from HNCO and HNCA spectra. Applied to experimental data from a challenging 34 kDa protein, RASP assigns 90 % of manually assigned residues using only 40 % of the experimental data required for the manual assignment. RASP has the potential to significantly accelerate the backbone assignment process for a wide range of proteins for which structural information is available, including those for which conventional assignment strategies are not feasible. PMID:24445369

  19. Effects of temperature on excluded volume-promoted cyclization and concatemerization of cohesive-ended DNA longer than 0.04 Mb.

    PubMed Central

    Louie, D; Serwer, P

    1991-01-01

    The 0.048502 megabase (Mb), primarily double-stranded DNA of bacteriophage lambda has single-stranded, complementary termini (cohesive ends) that undergo either spontaneous intramolecular joining to form open circular DNA or spontaneous intermolecular joining to form linear, end-to-end oligomeric DNAs (concatemers); concatemers also cyclize. In the present study, the effects of polyethylene glycol (PEG) on the cyclization and concatemerization of lambda DNA are determined at temperatures that, in the absence of PEG, favor dissociation of cohesive ends. Circular and linear lambda DNA, monomeric and concatemeric, are observed by use of pulsed field agarose gel (PFG) electrophoresis. During preparation of lambda DNA for these studies, hydrodynamic shear-induced, partial dissociation of joined cohesive ends is fortuitously observed. Although joined lambda cohesive ends progressively dissociate as their temperature is raised in the buffer used here (0.1 M NaCl, 0.01 M sodium phosphate, pH 7.4, 0.001 M EDTA), when PEG is added to this buffer, raising the temperature sometimes promotes joining of cohesive ends. Conditions for promotion of primarily either cyclization or concatemerization are described. Open circular DNAs as long as a 7-mer are produced and resolved. The concentration of PEG required to promote joining of cohesive ends decreases as the molecular weight of the PEG increases. The rate of cyclization is brought, the first time, to values that are high enough to be comparable to the rate observed in vivo. For double-stranded DNA bacteriophages that have a linear replicative form of DNA (bacteriophage T7, for example), a suppression, sometimes observed here, of cyclization mimics a suppression of cyclization previously observed in vivo. The PEG, temperature effects on DNA joining are explained by both the excluded volume of PEG random coils and an increase in this excluded volume that occurs when temperature increases. Images PMID:1829160

  20. Catalyst-Free Three-Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid, Amides, and DMSO by a Pummerer-Type Rearrangement.

    PubMed

    Wang, Peng-Min; Pu, Fan; Liu, Ke-Yan; Li, Chao-Jun; Liu, Zhong-Wen; Shi, Xian-Ying; Fan, Juan; Yang, Ming-Yu; Wei, Jun-Fa

    2016-04-25

    A catalyst-free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three-component tandem CDC cyclization by a Pummerer-type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp(2) )-H/C(sp(3) )-H cross-dehydrogenative coupling, C-N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant).

  1. Hg/Pt-catalyzed conversion of bromo alkynamines/alkynols to saturated and unsaturated γ-butyrolactams/lactones via intramolecular electrophilic cyclization.

    PubMed

    Kiran Kumar, Yalla; Ranjith Kumar, Gadi; Sridhar Reddy, Maddi

    2016-01-28

    Convenient and general Hg(ii)/Pt(iv) catalyzed syntheses of γ-butyrolactams and α,β-unsaturated γ-butyrolactones/lactams are described via intramolecular electrophilic cyclizations of bromoalkynes with tosylamino and hydroxyl tethers. The reaction features the use of wet solvents, the exclusion of any base and additive, mild conditions and practical yields. We also synthesised few chiral lactams through this pathway. Additionally, it is shown that the NHTs group distanced further from the homopropargylic position assists regioselective bromoalkyne hydration to yield useful α-bromoketones. Furthermore, Boc protected bromo homo propargyl amines undergo 6-endo-dig cyclization through Boc oxygen to give bromomethylene substituted oxazinones. PMID:26647118

  2. Doped Si nanoparticles with conformal carbon coating and cyclized-polyacrylonitrile network as high-capacity and high-rate lithium-ion battery anodes.

    PubMed

    Xie, Ming; Piper, Daniela Molina; Tian, Miao; Clancey, Joel; George, Steven M; Lee, Se-Hee; Zhou, Yun

    2015-09-11

    Doped Si nanoparticles (SiNPs) with conformal carbon coating and cyclized-polyacrylonitrile (PAN) network displayed capacities of 3500 and 3000 mAh g(-1) at C/20 and C/10, respectively. At 1 C, the electrode preserves a specific discharge capacity of ∼1500 mAh g(-1) for at least 60 cycles without decay. Al2O3 atomic layer deposition (ALD) helps improve the initial Coulombic efficiency (CE) to 85%. The dual coating of conformal carbon and cyclized-PAN help alleviate volume change and facilitate charge transfer. Ultra-thin Al2O3 ALD layers help form a stable solid electrolyte interphase interface.

  3. Stereoselective Synthesis of Spiro Bis-C,C-α-arylglycosides by Tandem Heck Type C-Glycosylation and Friedel-Crafts Cyclization.

    PubMed

    Chen, Yen-Bo; Liu, Shi-Hao; Hsieh, Min-Tsang; Chang, Chih-Shiang; Lin, Chun-Hung; Chen, Chen-Yin; Chen, Po-Yen; Lin, Hui-Chang

    2016-04-01

    Spiro bis-C,C-α-arylglycosides were synthesized in three steps in 78-85% overall yields starting from exo-glycals. The initial Heck type C-aryl addition of exo-glycals with arylboronic acids afforded α-aryl-β-substituted C-glycosides with exclusive α-stereoselectivity. Among the products, β-ethanal α-aryl C-glycosides further reacted with alkylthiol in the presence of InCl3, followed by in situ Friedel-Crafts cyclization to yield the desirable final products. We proposed a mechanism to explain how the α-aryl group serves as a main determinant of the cyclization. PMID:26986781

  4. Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven-Membered Lactones: Neutron Diffraction Study of the Stereoselective Deuteration of a Chiral Organosamarium Intermediate.

    PubMed

    Just-Baringo, Xavier; Clark, Jemma; Gutmann, Matthias J; Procter, David J

    2016-09-26

    Seven-membered lactones undergo selective SmI2 -H2 O-promoted radical cyclization to form substituted cyclooctanols. The products arise from an exo-mode of cyclization rather than the usual endo-attack employed in the few radical syntheses of cyclooctanes. The process is terminated by the quenching of a chiral benzylic samarium. A labeling experiment and neutron diffraction study have been used for the first time to probe the configuration and highly diastereoselective deuteration of a chiral organosamarium intermediate. PMID:27600354

  5. BF3·OEt2-Promoted Synthesis of 2,3-Metallocenocyclohexanones: A 1,2-Hydride Shift and Cationic Cyclization Strategy.

    PubMed

    He, Congfa; Wang, Jie; Gu, Zhenhua

    2015-08-21

    A BF3·OEt2-promoted cyclization of metallocenyl enones to form cyclohexanone-fused metallocenes is reported. 2,3-Metallocenocyclohexanones were formed exclusively, and no normal Nazarov-type cyclopentanone analogues were detected. The reaction possibly proceeded via an unusual cationic 1,2-hydride shift followed by Friedel-Crafts alkylative cyclization process. During the studies of the alkylation reaction of these keto esters, an unusual and rare facial selectivity was observed. The electrophiles would be attacked from the same face as the second Cp ring. PMID:26222272

  6. Multicomponent Double Diels-Alder/Nazarov Tandem Cyclization of Symmetric Cross-Conjugated Diynones to Generate [6-5-6] Tricyclic Products.

    PubMed

    Carmichael, Rachael A; Chalifoux, Wesley A

    2016-06-20

    The construction of complex polycyclic terpenoid products in an efficient and step-economical manner using multicomponent and tandem processes is highly valuable. Herein, we report a tandem cyclization sequence that initiates with a multicomponent double Diels-Alder reaction of cross-conjugated diynones, followed by a Nazarov cyclization to efficiently produce [6-5-6] tricyclic products with excellent regio- and diastereoselectivity. This methodology generates five new carbon-carbon bonds, three rings, quaternary or vicinal quaternary carbons, and stereogenic centers in a one-pot reaction. PMID:27124516

  7. Catalyst-Free Three-Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid, Amides, and DMSO by a Pummerer-Type Rearrangement.

    PubMed

    Wang, Peng-Min; Pu, Fan; Liu, Ke-Yan; Li, Chao-Jun; Liu, Zhong-Wen; Shi, Xian-Ying; Fan, Juan; Yang, Ming-Yu; Wei, Jun-Fa

    2016-04-25

    A catalyst-free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three-component tandem CDC cyclization by a Pummerer-type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp(2) )-H/C(sp(3) )-H cross-dehydrogenative coupling, C-N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant). PMID:26998754

  8. Synthesis of functionalized 5-substituted thiazolidine-2-thiones via adscititious xanthate-promoted radical cyclization of allyl(alkyl/aryl)dithiocarbamates.

    PubMed

    Gao, Simiao; Zhang, Yu; Dong, Jun; Chen, Ning; Xu, Jiaxi

    2016-01-21

    Functionalized 5-substituted thiazolidine-2-thiones were synthesized efficiently from alkyl allyl(alkyl/aryl)-dithiocarbamates via radical cyclization with the corresponding S-alkyl O-ethyl xanthates as the adscititious radical precursors. The application of the adscititious radical precursors improves not only the yields, but also the efficiency in the radical cyclization reaction significantly. The current adscititious radical precursor method provides a new strategy for the achievement and improvement of some radical reactions which are hardly or difficultly realized by the traditional direct methods. PMID:26626401

  9. Self-Relay Gold(I)-Catalyzed Pictet-Spengler/Cyclization Cascade Reaction for the Rapid Elaboration of Pentacyclic Indole Derivatives.

    PubMed

    Gobé, Valérian; Retailleau, Pascal; Guinchard, Xavier

    2015-12-01

    Gold-catalyzed cascade reactions allow the rapid elaboration of pentacyclic indolo[2,3-a]quinolizidines from N-allyl tryptamines and ortho-alkynylarylaldehydes. The tandem process combines a gold-catalyzed Pictet-Spengler reaction and a cyclization occurring concomitantly with an allyl transfer from the nitrogen atom to the stilbene function. Various substituted allyls were successfully transferred, furnishing the products in yields typically ranging from 60-98 % in high diastereoselectivity. Tryptamines bearing a butenol chain undergo an additional cyclization to chiral hemiaminals in high diastereoselectivities. PMID:26443069

  10. Doped Si nanoparticles with conformal carbon coating and cyclized-polyacrylonitrile network as high-capacity and high-rate lithium-ion battery anodes

    NASA Astrophysics Data System (ADS)

    Xie, Ming; Molina Piper, Daniela; Tian, Miao; Clancey, Joel; George, Steven M.; Lee, Se-Hee; Zhou, Yun

    2015-09-01

    Doped Si nanoparticles (SiNPs) with conformal carbon coating and cyclized-polyacrylonitrile (PAN) network displayed capacities of 3500 and 3000 mAh g-1 at C/20 and C/10, respectively. At 1 C, the electrode preserves a specific discharge capacity of ˜1500 mAh g-1 for at least 60 cycles without decay. Al2O3 atomic layer deposition (ALD) helps improve the initial Coulombic efficiency (CE) to 85%. The dual coating of conformal carbon and cyclized-PAN help alleviate volume change and facilitate charge transfer. Ultra-thin Al2O3 ALD layers help form a stable solid electrolyte interphase interface.

  11. Doped Si nanoparticles with conformal carbon coating and cyclized-polyacrylonitrile network as high-capacity and high-rate lithium-ion battery anodes.

    PubMed

    Xie, Ming; Piper, Daniela Molina; Tian, Miao; Clancey, Joel; George, Steven M; Lee, Se-Hee; Zhou, Yun

    2015-09-11

    Doped Si nanoparticles (SiNPs) with conformal carbon coating and cyclized-polyacrylonitrile (PAN) network displayed capacities of 3500 and 3000 mAh g(-1) at C/20 and C/10, respectively. At 1 C, the electrode preserves a specific discharge capacity of ∼1500 mAh g(-1) for at least 60 cycles without decay. Al2O3 atomic layer deposition (ALD) helps improve the initial Coulombic efficiency (CE) to 85%. The dual coating of conformal carbon and cyclized-PAN help alleviate volume change and facilitate charge transfer. Ultra-thin Al2O3 ALD layers help form a stable solid electrolyte interphase interface. PMID:26289444

  12. Inorganic backbone ionomers: Design and dielectric response of single-ion conducting polymers

    NASA Astrophysics Data System (ADS)

    Bartels, Joshua

    Ion-conducting polymers were studied primarily through the use of dielectric spectroscopy. The conclusions drawn from ion conduction models of the dielectric data are corroborated by additional independent experiments, including x-ray scattering, calorimetry, prism coupling, and DFT calculations. The broad concern of this dissertation is to understand and clarify a path forward in ion conducting polymer research. This is achieved by considering low-Tg ionomers and the advantages imparted by siloxane and phosphazene backbones. The most successful dielectric spectroscopy model for the materials studied is the electrode polarization model (EP), whereas other models, such as the Dyre random barrier model, fail to describe the experimental results. Seven nonionic ether oxygen (EO) containing polymers were studied in order to observe the effect that backbone chemistry has on dipole motion. Conventional carboncarbon backbone EO-containing polymers show no distinct advantage over similar EO-pendant polysiloxane or polyphosphazene systems. The mobility and effective backbone Tg imparted by the inorganic backbones are comparable. A short EO pendant results in a lower static dielectric constant due to restricted motion of dipoles close to the chain. The flexibility and chemical versatility of inorganic backbone polymers motivates further study of two ionomer systems. A polypohosphazene iodide conducting system was characterized by dielectric spectroscopy and x-ray scattering. Two end "tail" functionalization of the ammonium ion were used, a tail with two EOs and an alkyl tail of six carbons. This functional group plays an important role in ion dynamics and can wrap around the ion and self-solvate when EOs are present. The iodide-ammonium ionomers are observed to have unusually large high-frequency dielectric constants due to atomic polarization of ions. The strength of the atomic polarization scales with ion content. The aggregation state of ions is able to be determined from

  13. Triazole linkages and backbone branches in nucleic acids for biological and extra-biological applications

    NASA Astrophysics Data System (ADS)

    Paredes, Eduardo

    The recently increasing evidence of nucleic acids' alternative roles in biology and potential as useful nanomaterials and therapeutic agents has enabled the development of useful probes, elaborate nanostructures and therapeutic effectors based on nucleic acids. The study of alternative nucleic acid structure and function, particularly RNA, hinges on the ability to introduce site-specific modifications that either provide clues to the nucleic acid structure function relationship or alter the nucleic acid's function. Although the available chemistries allow for the conjugation of useful labels and molecules, their limitations lie in their tedious conjugation conditions or the lability of the installed probes. The development and optimization of click chemistry with RNA now provides the access to a robust and orthogonal conjugation methodology while providing stable conjugates. Our ability to introduce click reactive groups enzymatically, rather than only in the solid-phase, allows for the modification of larger, more cell relevant RNAs. Additionally, ligation of modified RNAs with larger RNA constructs through click chemistry represents an improvement over traditional ligation techniques. We determined that the triazole linkage generated through click chemistry is compatible in diverse nucleic acid based biological systems. Click chemistry has also been developed for extra-biological applications, particularly with DNA. We have expanded its use to generate useful polymer-DNA conjugates which can form controllable soft nanoparticles which take advantage of DNA's properties, i.e. DNA hybridization and computing. Additionally, we have generated protein-DNA conjugates and assembled protein-polymer hybrids mediated by DNA hybridization. The use of click chemistry in these reactions allows for the facile synthesis of these unnatural conjugates. We have also developed backbone branched DNA through click chemistry and showed that these branched DNAs are useful in generating

  14. Diminished oligomerization in the synthesis of new anti-angiogenic cyclic peptide using solution instead of solid-phase cyclization.

    PubMed

    Rubio, Sandra; Clarhaut, Jonathan; Péraudeau, Elodie; Vincenzi, Marian; Soum, Claire; Rossi, Filomena; Guillon, Jean; Papot, Sébastien; Ronga, Luisa

    2016-05-01

    The design and synthesis of novel peptides that inhibit angiogenesis is an important area for anti-angiogenic drug development. Cyclic and small peptides present several advantages for therapeutic application, including stability, solubility, increased bio-availability and lack of immune response in the host cell. We describe here the synthesis and biological evaluations of a new cyclic peptide analog of CBO-P11: cyclo(RIKPHE), designated herein as CBO-P23M, a hexamer peptide encompassing residues 82 to 86 of VEGF which are involved in the interaction with VEGF receptor-2. CBO-P23M was prepared using in solution cyclization, therefore reducing the peptide cyclodimerization occurred during solid-phase cyclization. The cyclic dimer of CBO-P23M, which was obtained as the main side product during synthesis of the corresponding monomer, was also isolated and investigated. Both peptides markedly reduce VEGF-A-induced phosphorylation of VEGFR-2 and Erk1/2. Moreover, they exhibit anti-angiogenic activity in an in vitro morphogenesis study. Therefore CBO-P23M and CBO-P23M dimer appear as attractive candidates for the development of novel angiogenesis inhibitors for the treatment of cancer and other angiogenesis-related diseases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 368-375, 2016.

  15. In vivo efficacy of anuran trypsin inhibitory peptides against staphylococcal skin infection and the impact of peptide cyclization.

    PubMed

    Malik, U; Silva, O N; Fensterseifer, I C M; Chan, L Y; Clark, R J; Franco, O L; Daly, N L; Craik, D J

    2015-04-01

    Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen. PMID:25624332

  16. Trajectory Calculations for Bergman Cyclization Predict H/D Kinetic Isotope Effects Due to Nonstatistical Dynamics in the Product.

    PubMed

    Doubleday, Charles; Boguslav, Mayla; Howell, Caronae; Korotkin, Scott D; Shaked, David

    2016-06-22

    An unusual H/D kinetic isotope effect (KIE) is described, in which isotopic selectivity arises primarily from nonstatistical dynamics in the product. In DFT-based quasiclassical trajectories of Bergman cyclization of (Z)-3-hexen-1,5-diyne (1) at 470 K, the new CC bond retains its energy, and 28% of nascent p-benzyne recrosses back to the enediyne on a vibrational time scale. The competing process of intramolecular vibrational redistribution (IVR) in p-benzyne is too slow to prevent this. Deuteration increases the rate of IVR, which decreases the fraction of recrossing and increases the yield of statistical (trapable) p-benzyne, 2. Trapable yields for three isotopomers of 2 range from 72% to 86%. The resulting KIEs for Bergman cyclization differ substantially from KIEs predicted by transition state theory, which suggests that IVR in this reaction can be studied by conventional KIEs. Leakage of vibrational zero point energy (ZPE) into the reaction coordinate was probed by trajectories in which initial ZPE in the CH/CD stretching modes was reduced by 25%. This did not change the predicted KIEs.

  17. Nonstatistical dynamics in the thermal C2-C6/diels-alder cyclization of enyne-allenes: effect of topology.

    PubMed

    Samanta, Debabrata; Rana, Anup; Schmittel, Michael

    2015-02-20

    The thermal C(2)-C(6) (Schmittel) cyclization of an enyne-allene with two aryl rings at the allene terminus experimentally leads to three formal Diels-Alder (DA) cycloaddition products, two of which (involving the dimethylamino phenyl unit) are shown to form in a nonstatistical process. DFT computations on the reaction paths reveal that the two aryl rings (Ph vs PhNMe2) do not interact in a dynamic manner as their minimum energy pathways (MEPs) are separated by a large barrier. The preferential formation of the more-hindered DA product 8 (ortho to the dimethylamino group) over the less-hindered product 9 (para to the dimethylamino group), despite the higher energy TS for 8, suggests the occurrence of nonstatistical dynamics in the cyclization onto the dimethylamino phenyl unit, though. Potential energy surface (PES) computations indicate that the large amount of nonstatistical dynamics (97%) arises from facile IRC dynamics (left picture) that is compared with the non-IRC dynamics of a related system (∼76%, right picture, J. Org. Chem. 2014, 79, 2368). PMID:25647469

  18. In vivo efficacy of anuran trypsin inhibitory peptides against staphylococcal skin infection and the impact of peptide cyclization.

    PubMed

    Malik, U; Silva, O N; Fensterseifer, I C M; Chan, L Y; Clark, R J; Franco, O L; Daly, N L; Craik, D J

    2015-04-01

    Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg(-1). Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.

  19. In Vivo Efficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

    PubMed Central

    Malik, U.; Silva, O. N.; Fensterseifer, I. C. M.; Chan, L. Y.; Clark, R. J.; Franco, O. L.; Daly, N. L.

    2015-01-01

    Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg−1. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen. PMID:25624332

  20. Backbone dependency further improves side chain prediction efficiency in the Energy-based Conformer Library (bEBL).

    PubMed

    Subramaniam, Sabareesh; Senes, Alessandro

    2014-11-01

    Side chain optimization is an integral component of many protein modeling applications. In these applications, the conformational freedom of the side chains is often explored using libraries of discrete, frequently occurring conformations. Because side chain optimization can pose a computationally intensive combinatorial problem, the nature of these conformer libraries is important for ensuring efficiency and accuracy in side chain prediction. We have previously developed an innovative method to create a conformer library with enhanced performance. The Energy-based Library (EBL) was obtained by analyzing the energetic interactions between conformers and a large number of natural protein environments from crystal structures. This process guided the selection of conformers with the highest propensity to fit into spaces that should accommodate a side chain. Because the method requires a large crystallographic data-set, the EBL was created in a backbone-independent fashion. However, it is well established that side chain conformation is strongly dependent on the local backbone geometry, and that backbone-dependent libraries are more efficient in side chain optimization. Here we present the backbone-dependent EBL (bEBL), whose conformers are independently sorted for each populated region of Ramachandran space. The resulting library closely mirrors the local backbone-dependent distribution of side chain conformation. Compared to the EBL, we demonstrate that the bEBL uses fewer conformers to produce similar side chain prediction outcomes, thus further improving performance with respect to the already efficient backbone-independent version of the library.

  1. Cationic Pd(II)-Catalyzed Cyclization of N-Tosyl-aniline Tethered Allenyl Aldehydes with Arylboronic Acids: Diastereo- and Enantioselective Synthesis of Tetrahydroquinoline Derivatives.

    PubMed

    Zhang, Xiaojuan; Han, Xiuling; Lu, Xiyan

    2015-08-01

    An efficient cyclization of N-tosyl-aniline tethered allenyl aldehydes and arylboronic acids catalyzed by cationic palladium complex is developed. This annulation reaction provides a convenient process for the synthesis of 3,4-cis-1,2,3,4-tetrahydroquinoline derivatives in high yields with excellent diastereoselectivity and enantioselectivity.

  2. Cyclic pentapeptide analogs based on endomorphin-2 structure: cyclization studies using liquid chromatography combined with on-line mass spectrometry and tandem mass spectrometry.

    PubMed

    Piekielna, Justyna; Kluczyk, Alicja; Perlikowska, Renata; Janecka, Anna

    2014-05-01

    The cyclization of linear analogs based on endomorphin-2 structure, Tyr/Dmt-d-Lys-Phe-Phe-Asp-NH2 and Tyr/Dmt-d-Cys-Phe-Phe-Cys-NH2 (where Dmt=2',6'-dimethyltyrosine), resulting in obtaining lactam or disulfide derivatives, was studied using liquid chromatography combined with on-line mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS). In case of cyclization via an amide bond, the formation of the cyclic monomers, cyclic but not linear dimers and even traces of cyclic trimers was observed. Disulfide bridge containing peptides was obtained by the solid-phase synthesis of the linear sequences, followed by either in-solution or on-resin cyclization. In case of the in-solution cyclization, the expected cyclic monomers were the only products. When oxidation of the cysteine residues was performed when the peptides were still on the resin, cyclic monomer and two cyclodimers, parallel and antiparallel, were found. Digestion of the isolated cyclodimers with α-chymotrypsin allowed for their unambiguous identification. The comparison of the cyclic monomer/dimer ratios for analogs with Tyr versus Dmt in position 1 revealed that the presence of the exocyclic Dmt favored formation of the cyclic monomer, most likely due to the increased steric bulk of this amino acid side-chain as compared with Tyr.

  3. Total synthesis of protosappanin A and its derivatives via palladium catalyzed ortho C-H activation/C-C cyclization under microwave irradiation.

    PubMed

    Liu, Jiaqi; Zhou, Xuan; Wang, Chenglong; Fu, Wanyong; Chu, Wenyi; Sun, Zhizhong

    2016-04-14

    A total synthesis method for protosappanin A, which is a complex natural product with many biological activities, was developed with 6 linear steps. Dibenzo[b,d]oxepinones as the key intermediates of the synthetic route were prepared by a palladium-catalyzed ortho C-H activation/C-C cyclization under microwave irradiation. 25 derivatives of protosappanin A were obtained. PMID:26997503

  4. Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid.

    PubMed

    Chung, John Y L; Cvetovich, Raymond; Amato, Joseph; McWilliams, J Christopher; Reamer, Robert; DiMichele, Lisa

    2005-04-29

    [reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.

  5. Discovery of hypoiodite-mediated aminyl radical cyclization lacking a nitrogen radical-stabilizing group: application to synthesis of an oxazaspiroketal-containing cephalostatin analog.

    PubMed

    Koag, Myong; Lee, Seongmin

    2011-09-16

    Synthesis of an oxazaspiroketal-containing bissteroidal pyrazine is described. The key transformation of this synthesis involves stereoselective formation of oxazaspiroketal via aminyl-radical cyclization of primary amine lacking a radical-stabilizing group by Suárez hypoiodite oxidation.

  6. Visible-Light-Promoted Dual C-C Bond Formations of Alkynoates via a Domino Radical Addition/Cyclization Reaction: A Synthesis of Coumarins.

    PubMed

    Feng, Shangbiao; Xie, Xingang; Zhang, Weiwei; Liu, Lin; Zhong, Zhuliang; Xu, Dengyu; She, Xuegong

    2016-08-01

    A visible-light-promoted, mild, and direct difunctionalization of alkynoates has been accomplished. This procedure provides a new strategy toward synthesis of the coumarin core structure by photoredox-mediated oxidation to generate the α-oxo radical, which supervenes a domino radical addition/cyclization reaction in moderate to good yields with high regioselectivity at ambient temperature.

  7. Carbonium vs. carbenium ion-like transition state geometries for carbocation cyclization – how strain associated with bridging affects 5-exo vs. 6-endo selectivity†

    PubMed Central

    Gutierrez, Osvaldo; Harrison, Jason G.; Felix, Ryan J.; Guzman, Fernando Cortés

    2013-01-01

    Quantum chemical calculations are used to explore the origins of regioselectivity for proton-, Pt(II)- and Pd(II)-promoted cyclizations of 1,5-hexadienes, 5-aminoalkenes, and allylic acetimidates. The strain associated with achieving carbonium ion-like transition state geometries is shown to be a key factor in controlling 5-exo vs. 6-endo selectivity. PMID:24404374

  8. Ruthenium(II)-catalyzed isomer-selective cyclization of 1,6-dienes leading to exo-methylenecyclopentanes: unprecedented cycloisomerization mechanism involving ruthenacyclopentane(hydrido) intermediate.

    PubMed

    Yamamoto, Y; Nakagai, Y I; Ohkoshi, N; Itoh, K

    2001-07-01

    In the presence of a catalytic amount of ruthenium(II) complexes, [RuCl(2)(cod)](n)(), RuCl(2)(cod)(MeCN)(2), [RuCl(2)(nbd)](n)(), [RuCl(2)(CO)(3)](2), and Cp*Ru(cod)Cl, 1,6-dienes were effectively converted into the corresponding exo-methylenecyclopentanes in good to excellent yields with good isomer purity in i-PrOH at 90 degrees C. The alcoholic solvent was essential for the present catalytic cyclization, and the efficiency increased in the following order: t-BuOH < EtOH < or = i-PrOH. In contrast, a Ru(0) complex, (C(6)Me(6))Ru(cod), catalyzed the cycloisomerization only in 1,2-dichloroethane. The unusual isomer-selectivity occurred when a 1,7-octadiene was subjected to cyclization to give a similar exo-methylenecyclopentane isomer as the major product. The identical isomer selectivity was observed for the cyclization of unsymmetrical 1,6-dienes having one terminal- and one internal-alkene termini. On the basis of the results from the studies using the known ruthenium hydrides and deuterium-labeling substrates, the novel mechanism via the Ru(II) <--> Ru(IV) system involving a ruthenacyclopentane(hydrido) intermediate was proposed, which better explains the particular regiochemistry of the present cyclization than other previous mechanisms. PMID:11427063

  9. [Investigation of the intramolecular cyclization of the thiophene substituted cyclohexane skeleton gamma-oxocarboxylic acid and synthesis of some N-heteroaryl isoindole derivatives].

    PubMed

    Csende, Ferenc

    2011-01-01

    From thiophene and cis-hexahydrophthalic anhydride the corresponding gamma-oxocarboxylic acid was obtained by the Friedel-Crafts reaction, which resulted in new heterocycles with acetic anhydride, Lawesson reagent or urea by intramolecular cyclization. Saturated N-heteroaryl isoindoles were prepared directly by the fusion reaction of heteroaromatic amines with the oxocarboxylic acid. PMID:21800711

  10. Asymmetric synthesis of tetrahydroquinolin-3-ols via CoCl2-catalyzed reductive cyclization of nitro cyclic sulfites with NaBH4.

    PubMed

    Jagdale, Arun R; Reddy, R Santhosh; Sudalai, Arumugam

    2009-02-19

    A new method for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on asymmetric dihydroxylation and CoCl(2)-catalyzed reductive cyclization of nitro cyclic sulfites with NaBH(4) has been described with high optical purities. This method has been successfully applied in the formal synthesis of PNU 95666E and anachelin H chromophore.

  11. Exposing Hidden Alternative Backbone Conformations in X-ray Crystallography Using qFit

    PubMed Central

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry

    2015-01-01

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Overall, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems. PMID:26506617

  12. Effect of Liquid-Crystalline Epoxy Backbone Structure on Thermal Conductivity of Epoxy-Alumina Composites

    NASA Astrophysics Data System (ADS)

    Giang, Thanhkieu; Kim, Jinhwan

    2016-06-01

    In a series of papers published recently, we clearly demonstrated that the most important factor governing the thermal conductivity of epoxy-Al2O3 composites is the backbone structure of the epoxy. In this study, three more epoxies based on diglycidyl ester-terminated liquid-crystalline epoxy (LCE) have been synthesized to draw conclusions regarding the effect of the epoxy backbone structure on the thermal conductivity of epoxy-alumina composites. The synthesized structures were characterized by proton nuclear magnetic resonance (1H-NMR) and Fourier-transform infrared (FT-IR) spectroscopy. Differential scanning calorimetry, thermogravimetric analysis, and optical microscopy were also employed to examine the thermal and optical properties of the synthesized LCEs and the cured composites. All three LCE resins exhibited typical liquid-crystalline behaviors: clear solid crystalline state below the melting temperature (T m), sharp crystalline melting at T m, and transition to nematic phase above T m with consequent isotropic phase above the isotropic temperature (T i). The LCE resins displayed distinct nematic liquid-crystalline phase over a wide temperature range and retained liquid-crystalline phase after curing, with high thermal conductivity of the resulting composite. The thermal conductivity values ranged from 3.09 W/m-K to 3.89 W/m-K for LCE-Al2O3 composites with 50 vol.% filler loading. The steric effect played a governing role in the difference. The neat epoxy resin thermal conductivity was obtained as 0.35 W/m-K to 0.49 W/m-K based on analysis using the Agari-Uno model. The results clearly support the objective of this study in that the thermal conductivity of the LCE-containing networks strongly depended on the epoxy backbone structure and the degree of ordering in the cured network.

  13. On the role of thermal backbone fluctuations in myoglobin ligand gate dynamics

    NASA Astrophysics Data System (ADS)

    Krokhotin, Andrey; Niemi, Antti J.; Peng, Xubiao

    2013-05-01

    We construct an energy function that describes the crystallographic structure of sperm whale myoglobin backbone. As a model in our construction, we use the Protein Data Bank entry 1ABS that has been measured at liquid helium temperature. Consequently, the thermal B-factor fluctuations are very small, which is an advantage in our construction. The energy function that we utilize resembles that of the discrete nonlinear Schrödinger equation. Likewise, ours supports topological solitons as local minimum energy configurations. We describe the 1ABS backbone in terms of topological solitons with a precision that deviates from 1ABS by an average root-mean-square distance, which is less than the experimentally observed Debye-Waller B-factor fluctuation distance. We then subject the topological multi-soliton solution to extensive numerical heating and cooling experiments, over a very wide range of temperatures. We concentrate in particular to temperatures above 300 K and below the Θ-point unfolding temperature, which is around 348 K. We confirm that the behavior of the topological multi-soliton is fully consistent with Anfinsen's thermodynamic principle, up to very high temperatures. We observe that the structure responds to an increase of temperature consistently in a very similar manner. This enables us to characterize the onset of thermally induced conformational changes in terms of three distinct backbone ligand gates. One of the gates is made of the helix F and the helix E. The two other gates are chosen similarly, when open they provide a direct access route for a ligand to reach the heme. We find that out of the three gates we investigate, the one which is formed by helices B and G is the most sensitive to thermally induced conformational changes. Our approach provides a novel perspective to the important problem of ligand entry and exit.

  14. On the role of thermal backbone fluctuations in myoglobin ligand gate dynamics.

    PubMed

    Krokhotin, Andrey; Niemi, Antti J; Peng, Xubiao

    2013-05-01

    We construct an energy function that describes the crystallographic structure of sperm whale myoglobin backbone. As a model in our construction, we use the Protein Data Bank entry 1ABS that has been measured at liquid helium temperature. Consequently, the thermal B-factor fluctuations are very small, which is an advantage in our construction. The energy function that we utilize resembles that of the discrete nonlinear Schrödinger equation. Likewise, ours supports topological solitons as local minimum energy configurations. We describe the 1ABS backbone in terms of topological solitons with a precision that deviates from 1ABS by an average root-mean-square distance, which is less than the experimentally observed Debye-Waller B-factor fluctuation distance. We then subject the topological multi-soliton solution to extensive numerical heating and cooling experiments, over a very wide range of temperatures. We concentrate in particular to temperatures above 300 K and below the Θ-point unfolding temperature, which is around 348 K. We confirm that the behavior of the topological multi-soliton is fully consistent with Anfinsen's thermodynamic principle, up to very high temperatures. We observe that the structure responds to an increase of temperature consistently in a very similar manner. This enables us to characterize the onset of thermally induced conformational changes in terms of three distinct backbone ligand gates. One of the gates is made of the helix F and the helix E. The two other gates are chosen similarly, when open they provide a direct access route for a ligand to reach the heme. We find that out of the three gates we investigate, the one which is formed by helices B and G is the most sensitive to thermally induced conformational changes. Our approach provides a novel perspective to the important problem of ligand entry and exit. PMID:23656161

  15. ngs_backbone: a pipeline for read cleaning, mapping and SNP calling using Next Generation Sequence

    PubMed Central

    2011-01-01

    Background The possibilities offered by next generation sequencing (NGS) platforms are revolutionizing biotechnological laboratories. Moreover, the combination of NGS sequencing and affordable high-throughput genotyping technologies is facilitating the rapid discovery and use of SNPs in non-model species. However, this abundance of sequences and polymorphisms creates new software needs. To fulfill these needs, we have developed a powerful, yet easy-to-use application. Results The ngs_backbone software is a parallel pipeline capable of analyzing Sanger, 454, Illumina and SOLiD (Sequencing by Oligonucleotide Ligation and Detection) sequence reads. Its main supported analyses are: read cleaning, transcriptome assembly and annotation, read mapping and single nucleotide polymorphism (SNP) calling and selection. In order to build a truly useful tool, the software development was paired with a laboratory experiment. All public tomato Sanger EST reads plus 14.2 million Illumina reads were employed to test the tool and predict polymorphism in tomato. The cleaned reads were mapped to the SGN tomato transcriptome obtaining a coverage of 4.2 for Sanger and 8.5 for Illumina. 23,360 single nucleotide variations (SNVs) were predicted. A total of 76 SNVs were experimentally validated, and 85% were found to be real. Conclusions ngs_backbone is a new software package capable of analyzing sequences produced by NGS technologies and predicting SNVs with great accuracy. In our tomato example, we created a highly polymorphic collection of SNVs that will be a useful resource for tomato researchers and breeders. The software developed along with its documentation is freely available under the AGPL license and can be downloaded from http://bioinf.comav.upv.es/ngs_backbone/ or http://github.com/JoseBlanca/franklin. PMID:21635747

  16. Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions.

    PubMed

    Botan, Alexandru; Favela-Rosales, Fernando; Fuchs, Patrick F J; Javanainen, Matti; Kanduč, Matej; Kulig, Waldemar; Lamberg, Antti; Loison, Claire; Lyubartsev, Alexander; Miettinen, Markus S; Monticelli, Luca; Määttä, Jukka; Ollila, O H Samuli; Retegan, Marius; Róg, Tomasz; Santuz, Hubert; Tynkkynen, Joona

    2015-12-10

    Phospholipids are essential building blocks of biological membranes. Despite a vast amount of very accurate experimental data, the atomistic resolution structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resolution molecular dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the experimental data, but only if the simulations reproduce the data within experimental accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR experiments in terms of the highly structurally sensitive C-H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resolution structural accuracy of the models. Accurate models, in turn, allow molecular dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three-dimensional representation of biomolecules in biologically relevant conditions. In addition to lipid bilayers in fully hydrated conditions, we reviewed previous experimental data for dehydrated bilayers and cholesterol-containing bilayers, and interpreted them with simulations. Although none of the existing models reached experimental accuracy, by critically comparing them we were able to distill relevant chemical information: (1) increase of choline order parameters indicates the P-N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files ( https

  17. Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions.

    PubMed

    Botan, Alexandru; Favela-Rosales, Fernando; Fuchs, Patrick F J; Javanainen, Matti; Kanduč, Matej; Kulig, Waldemar; Lamberg, Antti; Loison, Claire; Lyubartsev, Alexander; Miettinen, Markus S; Monticelli, Luca; Määttä, Jukka; Ollila, O H Samuli; Retegan, Marius; Róg, Tomasz; Santuz, Hubert; Tynkkynen, Joona

    2015-12-10

    Phospholipids are essential building blocks of biological membranes. Despite a vast amount of very accurate experimental data, the atomistic resolution structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resolution molecular dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the experimental data, but only if the simulations reproduce the data within experimental accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR experiments in terms of the highly structurally sensitive C-H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resolution structural accuracy of the models. Accurate models, in turn, allow molecular dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three-dimensional representation of biomolecules in biologically relevant conditions. In addition to lipid bilayers in fully hydrated conditions, we reviewed previous experimental data for dehydrated bilayers and cholesterol-containing bilayers, and interpreted them with simulations. Although none of the existing models reached experimental accuracy, by critically comparing them we were able to distill relevant chemical information: (1) increase of choline order parameters indicates the P-N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files ( https

  18. Toward Atomistic Resolution Structure of Phosphatidylcholine Headgroup and Glycerol Backbone at Different Ambient Conditions†

    PubMed Central

    2015-01-01

    Phospholipids are essential building blocks of biological membranes. Despite a vast amount of very accurate experimental data, the atomistic resolution structures sampled by the glycerol backbone and choline headgroup in phoshatidylcholine bilayers are not known. Atomistic resolution molecular dynamics simulations have the potential to resolve the structures, and to give an arrestingly intuitive interpretation of the experimental data, but only if the simulations reproduce the data within experimental accuracy. In the present work, we simulated phosphatidylcholine (PC) lipid bilayers with 13 different atomistic models, and compared simulations with NMR experiments in terms of the highly structurally sensitive C–H bond vector order parameters. Focusing on the glycerol backbone and choline headgroups, we showed that the order parameter comparison can be used to judge the atomistic resolution structural accuracy of the models. Accurate models, in turn, allow molecular dynamics simulations to be used as an interpretation tool that translates these NMR data into a dynamic three-dimensional representation of biomolecules in biologically relevant conditions. In addition to lipid bilayers in fully hydrated conditions, we reviewed previous experimental data for dehydrated bilayers and cholesterol-containing bilayers, and interpreted them with simulations. Although none of the existing models reached experimental accuracy, by critically comparing them we were able to distill relevant chemical information: (1) increase of choline order parameters indicates the P–N vector tilting more parallel to the membrane, and (2) cholesterol induces only minor changes to the PC (glycerol backbone) structure. This work has been done as a fully open collaboration, using nmrlipids.blogspot.fi as a communication platform; all the scientific contributions were made publicly on this blog. During the open research process, the repository holding our simulation trajectories and files (https

  19. RNA backbone: Consensus all-angle conformers and modular string nomenclature (an RNA Ontology Consortium contribution)

    PubMed Central

    Richardson, Jane S.; Schneider, Bohdan; Murray, Laura W.; Kapral, Gary J.; Immormino, Robert M.; Headd, Jeffrey J.; Richardson, David C.; Ham, Daniela; Hershkovits, Eli; Williams, Loren Dean; Keating, Kevin S.; Pyle, Anna Marie; Micallef, David; Westbrook, John; Berman, Helen M.

    2008-01-01

    A consensus classification and nomenclature are defined for RNA backbone structure using all of the backbone torsion angles. By a consensus of several independent analysis methods, 46 discrete conformers are identified as suitably clustered in a quality-filtered, multidimensional dihedral angle distribution. Most of these conformers represent identifiable features or roles within RNA structures. The conformers are given two-character names that reflect the seven-angle δεζαβγδ combinations empirically found favorable for the sugar-to-sugar “suite” unit within which the angle correlations are strongest (e.g., 1a for A-form, 5z for the start of S-motifs). Since the half-nucleotides are specified by a number for δεζ and a lowercase letter for αβγδ, this modular system can also be parsed to describe traditional nucleotide units (e.g., a1) or the dinucleotides (e.g., a1a1) that are especially useful at the level of crystallographic map fitting. This nomenclature can also be written as a string with two-character suite names between the uppercase letters of the base sequence (N1aG1gN1aR1aA1cN1a for a GNRA tetraloop), facilitating bioinformatic comparisons. Cluster means, standard deviations, coordinates, and examples are made available, as well as the Suitename software that assigns suite conformer names and conformer match quality (suiteness) from atomic coordinates. The RNA Ontology Consortium will combine this new backbone system with others that define base pairs, base-stacking, and hydrogen-bond relationships to provide a full description of RNA structural motifs. PMID:18192612

  20. Exposing hidden alternative backbone conformations in X-ray crystallography using qFit

    SciTech Connect

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry; Shehu, Amarda

    2015-10-27

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechain conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.

  1. Exposing hidden alternative backbone conformations in X-ray crystallography using qFit

    DOE PAGES

    Keedy, Daniel A.; Fraser, James S.; van den Bedem, Henry; Shehu, Amarda

    2015-10-27

    Proteins must move between different conformations of their native ensemble to perform their functions. Crystal structures obtained from high-resolution X-ray diffraction data reflect this heterogeneity as a spatial and temporal conformational average. Although movement between natively populated alternative conformations can be critical for characterizing molecular mechanisms, it is challenging to identify these conformations within electron density maps. Alternative side chain conformations are generally well separated into distinct rotameric conformations, but alternative backbone conformations can overlap at several atomic positions. Our model building program qFit uses mixed integer quadratic programming (MIQP) to evaluate an extremely large number of combinations of sidechainmore » conformers and backbone fragments to locally explain the electron density. Here, we describe two major modeling enhancements to qFit: peptide flips and alternative glycine conformations. We find that peptide flips fall into four stereotypical clusters and are enriched in glycine residues at the n+1 position. The potential for insights uncovered by new peptide flips and glycine conformations is exemplified by HIV protease, where different inhibitors are associated with peptide flips in the “flap” regions adjacent to the inhibitor binding site. Our results paint a picture of peptide flips as conformational switches, often enabled by glycine flexibility, that result in dramatic local rearrangements. Our results furthermore demonstrate the power of large-scale computational analysis to provide new insights into conformational heterogeneity. Furthermore, improved modeling of backbone heterogeneity with high-resolution X-ray data will connect dynamics to the structure-function relationship and help drive new design strategies for inhibitors of biomedically important systems.« less

  2. Backbone resonance assignments for the SET domain of the human methyltransferase NSD2.

    PubMed

    Bobby, Romel; Peciak, Karolina; Milbradt, Alexander G

    2016-10-01

    Aberrant NSD2 methyltransferase activity is implicated as the oncogenic driver in multiple myeloma, suggesting opportunities for novel therapeutic intervention. The methyltransferase activity of NSD2 resides in its catalytic SET domain, which is conserved among most lysine methyltransferases. Here we report the backbone [Formula: see text], N, C[Formula: see text], [Formula: see text] and side-chain [Formula: see text] assignments of a 25 kDa NSD2 SET domain construct, spanning residues 991-1203. A chemical shift analysis of C[Formula: see text], [Formula: see text] and [Formula: see text] resonances predicts a secondary structural pattern that is in agreement with homology models.

  3. Backbone resonance assignments of the α sub-domain of Brevibacillus thermoruber Lon protease.

    PubMed

    Chen, Yu-Da; Wu, Shih-Hsiung; Hsu, Chun-Hua

    2014-10-01

    Lon is an ATPases associated with diverse cellular activities protease and belongs to a unique group that binds DNA. The α sub-domain of Lon protease is responsible for DNA-binding, but the structural information for its DNA-recognition mode is still limited. Here, we report (1)H, (15)N and (13)C backbone assignment for the α sub-domain from Brevibacillus thermoruber Lon protease as the basis for the elucidation of its structure and interactions with DNA, necessary for understanding the allosteric regulatory mechanism of the enzymatic function.

  4. Integrating the university medical center. Phase one: providing an information backbone.

    PubMed Central

    Berry, S. J.; Reber, E.; Offeman, W. E.

    1991-01-01

    UCLA School of Medicine represents a diverse computing community where the creation of each individual network has been driven by applications, price/performance and functionality. Indeed, the ability to connect to other computers has had no bearing on selection. Yet, there exists a need to seamlessly connect the individual networks to other minicomputers, mainframes and remote computers. We have created a school wide backbone network that will enable an individual from a single workstation to access a wide variety of services residing on any number of machines. PMID:1807658

  5. Molecular mechanical studies of DNA flexibility: coupled backbone torsion angles and base-pair openings.

    PubMed

    Keepers, J W; Kollman, P A; Weiner, P K; James, T L

    1982-09-01

    Molecular mechanics studies have been carried out on "B-DNA-like" structures of [d(C-G-C-G-A-A-T-T-C-G-C-G)](2) and [d(A)](12).[d(T)](12). Each of the backbone torsion angles (psi, phi, omega, omega', phi') has been "forced" to alternative values from the normal B-DNA values (g(+), t, g(-), g(-), t conformations). Compensating torsion angle changes preserve most of the base stacking energy in the double helix. In a second part of the study, one purine N3-pyrimidine N1 distance at a time has been forced to a value of 6 A in an attempt to simulate the base opening motions required to rationalize proton exchange data for DNA. When the 6-A constraint is removed, many of the structures revert to the normal Watson-Crick hydrogen-bonded structure, but a number are trapped in structures approximately 5 kcal/mol higher in energy than the starting B-DNA structure. The relative energy of these structures, some of which involve a non-Watson-Crick thymine C2(carbonyl)[unk]adenine 6NH(2) hydrogen bond, are qualitatively consistent with the DeltaH for a "base pair-open state" suggested by Mandal et al. of 4-6 kcal/mol [Mandal, C., Kallenbach, N. R. & Englander, S. W. (1979) J. Mol. Biol. 135, 391-411]. The picture of DNA flexibility emerging from this study depicts the backbone as undergoing rapid motion between local torsional minima on a nanosecond time scale. Backbone motion is mainly localized within a dinucleoside segment and generally not conformationally coupled along the chain or across the base pairs. Base motions are much smaller in magnitude than backbone motions. Base sliding allows imino N-H exchange, but it is localized, and only a small fraction of the N-H groups is exposed at any one time. Stacking and hydrogen bonding cause a rigid core of bases in the center of the molecule accounting for the hydrodynamic properties of DNA.

  6. Computer assignment of the backbone resonances of labelled proteins using two-dimensional correlation experiments.

    PubMed

    Morelle, N; Brutscher, B; Simorre, J P; Marion, D

    1995-02-01

    We present ALPS (Assignment for Labelled Protein Spectra), a flexible computer program for the automatic assignment of backbone NMR resonances of (15)N/(13)C-labelled proteins. The program constructs pseudoresidues from peak-picking lists of a set of two-dimensional triple resonance experiments and uses either a systematic search or a simulated annealing-based optimization to perform the assignment. This method has been successfully tested on two-dimensional triple resonance spectra of Rhodobacter capsulatus ferrocytochrome c (2) (116 amino acids).

  7. Development of metal-containing polymers for optoelectronic applications

    NASA Astrophysics Data System (ADS)

    Chan, Wai Kin; Hou, Sijian; Ng, Po K.; Wong, Chi T.; Yu, Sze C.

    1999-11-01

    Most of the work in organic electroluminescent polymers has been focused on organic conjugated polymers. However, polymers attached with transition metal complex have received relatively less attention. We have synthesized and studied the light emitting properties of some metal containing polymers based on the polypyridine complexes of rhenium and ruthenium. These complexes exhibit long-lived excited states caused by the metal to ligand charge transfer transitions. By varying the structure of the ligand and/or the transition metal, we are able to fine-tune the electronic properties of the resulting metal complexes. We have synthesized a series of poly(phenylenevinylene) (PPV) derivatives which are functionalized with ruthenium polypyridine complexes at the polymer mainchain or side chain. These complexes are able to act as photosensitizers which enhance the photoconductivity of these polymers at longer wavelength. Both the conjugated backbone and the metal complex can emit light upon excitation. As a result, it is possible to tune the color by loading different amount of ruthenium complex to the polymer. Luminescence studies showed that the ruthenium complex could quench the emission of the conjugated backbone in some polymers, which suggests an energy transfer process between the backbone and the metal complexes. It was also found that the presence of metal complexes could enhance the charge carrier mobilities of the polymers, as the metal and/or ligands can act as extra charge carriers in the charge transport process.

  8. Metal Preferences and Metallation*

    PubMed Central

    Foster, Andrew W.; Osman, Deenah; Robinson, Nigel J.

    2014-01-01

    The metal binding preferences of most metalloproteins do not match their metal requirements. Thus, metallation of an estimated 30% of metalloenzymes is aided by metal delivery systems, with ∼25% acquiring preassembled metal cofactors. The remaining ∼70% are presumed to compete for metals from buffered metal pools. Metallation is further aided by maintaining the relative concentrations of these pools as an inverse function of the stabilities of the respective metal complexes. For example, magnesium enzymes always prefer to bind zinc, and these metals dominate the metalloenzymes without metal delivery systems. Therefore, the buffered concentration of zinc is held at least a million-fold below magnesium inside most cells. PMID:25160626

  9. Generation of transgenic Drosophila expressing shRNAs in the miR-1 backbone.

    PubMed

    Chang, Kenneth; Marran, Krista; Valentine, Amy; Hannon, Gregory J

    2014-05-01

    In Drosophila, long-term effects of RNA interference (RNAi) must be achieved by integrating into the genome a template from which an RNAi trigger is transcribed by cellular RNA polymerases, generally RNA polymerase II or III. With encoded triggers, not only can essentially permanent silencing be achieved, but control can also be exerted over the level of trigger expression, with a resulting variation in the degree to which the target is silenced. Knockdown can also be controlled in a temporal and cell-type-dependent fashion through the use of well-established transgenic methodologies and well-tested promoters. The forms of encoded triggers vary. Long double-stranded RNAs can be expressed as extended inverted repeats. The nearest equivalent of a small interfering RNA is an artificial microRNA (miRNA) or short hairpin RNA (shRNA), where a natural miRNA backbone (also called a scaffold) is remodeled to produce a different small RNA or a small inverted repeat (<30 nucleotides) is simply expressed. This protocol describes creation of transgenic Drosophila carrying shRNA inserts in a remodeled endogenous miRNA backbone. The protocol applies to the use of miRNA-based shRNAs, but most of the vectors, principles of experimental design, and methods are also applicable to long inverted repeat transgenes. PMID:24786506

  10. BEST-HNN and 2D-(HN) NH experiments for rapid backbone assignment in proteins

    NASA Astrophysics Data System (ADS)

    Kumar, Dinesh; Paul, Subhradip; Hosur, Ramakrishna V.

    2010-05-01

    HNN has proven to be an extremely valuable experiment for rapid and unambiguous backbone (H N, 15N) assignment in ( 13C, 15N) labeled proteins. However, low sensitivity of the experiment is often a limiting factor, especially when the transverse relaxation times ( T2) are short. We show here that BEST modification Schanda et al. (2006) [2] increases the sensitivity per unit time by more than a factor of 2.0 and thus substantially increases the speed of data collection; good 3D data can be collected in 8-10 h. Next, we present a simple method for amino-acid type identification based on simple 2D versions of the HNN experiment, labeled here as 2D-(HN) NH. Each of these experiments which produce anchor points for Gly, Ala, Ser/Thr residues, can be recorded in less than an hour. These enable rapid data acquisition, rapid analysis, and consequently rapid assignment of backbone (H N, 15N) resonances. The 2D-(HN) NH experiment does not involve aliphatic/aromatic protons and hence can be applied to deuterated protein samples as well, which is an additional advantage. The experiments have been demonstrated with human ubiquitin (76 aa) and acetic-acid denatured HIV-1 protease (99 aa), as representatives of folded and unfolded protein systems, respectively.

  11. TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts.

    PubMed

    Shen, Yang; Delaglio, Frank; Cornilescu, Gabriel; Bax, Ad

    2009-08-01

    NMR chemical shifts in proteins depend strongly on local structure. The program TALOS establishes an empirical relation between 13C, 15N and 1H chemical shifts and backbone torsion angles phi and psi (Cornilescu et al. J Biomol NMR 13 289-302, 1999). Extension of the original 20-protein database to 200 proteins increased the fraction of residues for which backbone angles could be predicted from 65 to 74%, while reducing the error rate from 3 to 2.5%. Addition of a two-layer neural network filter to the database fragment selection process forms the basis for a new program, TALOS+, which further enhances the prediction rate to 88.5%, without increasing the error rate. Excluding the 2.5% of residues for which TALOS+ makes predictions that strongly differ from those observed in the crystalline state, the accuracy of predicted phi and psi angles, equals +/-13 degrees . Large discrepancies between predictions and crystal structures are primarily limited to loop regions, and for the few cases where multiple X-ray structures are available such residues are often found in different states in the different structures. The TALOS+ output includes predictions for individual residues with missing chemical shifts, and the neural network component of the program also predicts secondary structure with good accuracy.

  12. Optimization of Protein Backbone Dihedral Angles by Means of Hamiltonian Reweighting

    PubMed Central

    2016-01-01

    Molecular dynamics simulations depend critically on the accuracy of the underlying force fields in properly representing biomolecules. Hence, it is crucial to validate the force-field parameter sets in this respect. In the context of the GROMOS force field, this is usually achieved by comparing simulation data to experimental observables for small molecules. In this study, we develop new amino acid backbone dihedral angle potential energy parameters based on the widely used 54A7 parameter set by matching to experimental J values and secondary structure propensity scales. In order to find the most appropriate backbone parameters, close to 100 000 different combinations of parameters have been screened. However, since the sheer number of combinations considered prohibits actual molecular dynamics simulations for each of them, we instead predicted the values for every combination using Hamiltonian reweighting. While the original 54A7 parameter set fails to reproduce the experimental data, we are able to provide parameters that match significantly better. However, to ensure applicability in the context of larger peptides and full proteins, further studies have to be undertaken. PMID:27559757

  13. Di-Isocyanate Crosslinked Aerogels with 1, 6-Bis (Trimethoxysilyl) Hexane Incorporated in Silica Backbone

    NASA Technical Reports Server (NTRS)

    Vivod, Stephanie L.; Meador, Mary Ann B.; Nguyen, Baochau N.; Quade, Derek; Randall, Jason; Perry, Renee

    2008-01-01

    Silica aerogels are desirable materials for many applications that take advantage of their light weight and low thermal conductivity. Addition of a conformal polymer coating which bonds with the amine decorated surface of the silica network improves the strength of the aerogels by as much as 200 times. Even with vast improvement in strength they still tend to undergo brittle failure due to the rigid silica backbone. We hope to increase the flexibility and elastic recovery of the silica based aerogel by altering the silica back-bone by incorporation of more flexible hexane links. To this end, we investigated the use of 1,6-bis(trimethoxysilyl)hexane (BTMSH), a polysilsesquioxane precursor3, as an additional co-reactant to prepare silica gels which were subsequently cross-linked with di-isocyanate. Previously, this approach of adding flexibility by BTMSH incorporation was demonstrated with styrene cross-linked aerogels. In our study, we varied silane concentration, mol % of silicon from BTMSH and di-isocyanate concentration by weight percent to attempt to optimize both the flexibility and the strength of the aerogels.

  14. RNA-Redesign: a web server for fixed-backbone 3D design of RNA.

    PubMed

    Yesselman, Joseph D; Das, Rhiju

    2015-07-01

    RNA is rising in importance as a design medium for interrogating fundamental biology and for developing therapeutic and bioengineering applications. While there are several online servers for design of RNA secondary structure, there are no tools available for the rational design of 3D RNA structure. Here we present RNA-Redesign (http://rnaredesign.stanford.edu), an online 3D design tool for RNA. This resource utilizes fixed-backbone design to optimize the sequence identity and nucleobase conformations of an RNA to match a desired backbone, analogous to fundamental tools that underlie rational protein engineering. The resulting sequences suggest thermostabilizing mutations that can be experimentally verified. Further, sequence preferences that differ between natural and computationally designed sequences can suggest whether natural sequences possess functional constraints besides folding stability, such as cofactor binding or conformational switching. Finally, for biochemical studies, the designed sequences can suggest experimental tests of 3D models, including concomitant mutation of base triples. In addition to the designs generated, detailed graphical analysis is presented through an integrated and user-friendly environment.

  15. The structure of the carbohydrate backbone of the lipopolysaccharide of Pectinatus frisingensis strain VTT E-79104.

    PubMed

    Vinogradov, Evgeny; Li, Jianjun; Sadovskaya, Irina; Jabbouri, Said; Helander, Ilkka M

    2004-06-22

    The structure of the carbohydrate backbone of the lipopolysaccharide from Pectinatus frisingensis strain VTT E-79104 was analyzed using chemical degradations, NMR spectroscopy, mass spectrometry, and chemical methods. The LPS contains two major structural variants, differing in the presence or absence of an octasaccharide fragment. The largest structure of the carbohydrate backbone of the LPS, that could be deduced from experimental results, consists of 20 monosaccharides arranged in a nonrepetitive sequence: [carbohydrate structure: see text] where R is H or 4-O-Me-alpha-L-Fuc-(1-2)-4-O-Me-beta-Hep-(1-3)-alpha-GlcNAc-(1-2)-beta-Man-(1-3)-beta-ManNAc-(1-4)-alpha-Gal-(1-4)-beta-Hep-(1-3)-beta-GalNAc-(1- where Hep is a residue of D-glycero-D-galacto-heptose; all monosaccharides have the D-configuration except for 4-O-Me-L-Fuc and L-Ara4N. This structure is architecturally similar to the oligosaccharide system reported previously in P. frisingensis VTT E-82164 LPS, but differs from the latter in composition and also in the size of the outer region.

  16. First-principles study of the effect of functional groups on polyaniline backbone

    PubMed Central

    Chen, X. P.; Jiang, J. K.; Liang, Q. H.; Yang, N.; Ye, H. Y.; Cai, M.; Shen, L.; Yang, D. G.; Ren, T. L.

    2015-01-01

    We present a first-principles density functional theory study focused on how the chemical and electronic properties of polyaniline are adjusted by introducing suitable substituents on a polymer backbone. Analyses of the obtained energy barriers, reaction energies and minimum energy paths indicate that the chemical reactivity of the polyaniline derivatives is significantly enhanced by protonic acid doping of the substituted materials. Further study of the density of states at the Fermi level, band gap, HOMO and LUMO shows that both the unprotonated and protonated states of these polyanilines are altered to different degrees depending on the functional group. We also note that changes in both the chemical and electronic properties are very sensitive to the polarity and size of the functional group. It is worth noting that these changes do not substantially alter the inherent chemical and electronic properties of polyaniline. Our results demonstrate that introducing different functional groups on a polymer backbone is an effective approach to obtain tailored conductive polymers with desirable properties while retaining their intrinsic properties, such as conductivity. PMID:26584671

  17. Conformation-dependent backbone geometry restraints set a new standard for protein crystallographic refinement

    DOE PAGES

    Moriarty, Nigel W.; Tronrud, Dale E.; Adams, Paul D.; Karplus, P. Andrew

    2014-06-17

    Ideal values of bond angles and lengths used as external restraints are crucial for the successful refinement of protein crystal structures at all but the highest of resolutions. The restraints in common usage today have been designed based on the assumption that each type of bond or angle has a single ideal value independent of context. However, recent work has shown that the ideal values are, in fact, sensitive to local conformation, and as a first step toward using such information to build more accurate models, ultra-high resolution protein crystal structures have been used to derive a conformation-dependent library (CDL)more » of restraints for the protein backbone (Berkholz et al. 2009. Structure. 17, 1316). Here, we report the introduction of this CDL into the Phenix package and the results of test refinements of thousands of structures across a wide range of resolutions. These tests show that use of the conformation dependent library yields models that have substantially better agreement with ideal main-chain bond angles and lengths and, on average, a slightly enhanced fit to the X-ray data. No disadvantages of using the backbone CDL are apparent. In Phenix usage of the CDL can be selected by simply specifying the cdl=True option. This successful implementation paves the way for further aspects of the context-dependence of ideal geometry to be characterized and applied to improve experimental and predictive modelling accuracy.« less

  18. Conformation-dependent backbone geometry restraints set a new standard for protein crystallographic refinement

    SciTech Connect

    Moriarty, Nigel W.; Tronrud, Dale E.; Adams, Paul D.; Karplus, P. Andrew

    2014-06-17

    Ideal values of bond angles and lengths used as external restraints are crucial for the successful refinement of protein crystal structures at all but the highest of resolutions. The restraints in common usage today have been designed based on the assumption that each type of bond or angle has a single ideal value independent of context. However, recent work has shown that the ideal values are, in fact, sensitive to local conformation, and as a first step toward using such information to build more accurate models, ultra-high resolution protein crystal structures have been used to derive a conformation-dependent library (CDL) of restraints for the protein backbone (Berkholz et al. 2009. Structure. 17, 1316). Here, we report the introduction of this CDL into the Phenix package and the results of test refinements of thousands of structures across a wide range of resolutions. These tests show that use of the conformation dependent library yields models that have substantially better agreement with ideal main-chain bond angles and lengths and, on average, a slightly enhanced fit to the X-ray data. No disadvantages of using the backbone CDL are apparent. In Phenix usage of the CDL can be selected by simply specifying the cdl=True option. This successful implementation paves the way for further aspects of the context-dependence of ideal geometry to be characterized and applied to improve experimental and predictive modelling accuracy.

  19. The Nanomechanical Properties of Lactococcus lactis Pili Are Conditioned by the Polymerized Backbone Pilin

    PubMed Central

    Castelain, Mickaël; Duviau, Marie-Pierre; Canette, Alexis; Schmitz, Philippe; Loubière, Pascal; Cocaign-Bousquet, Muriel; Piard, Jean-Christophe; Mercier-Bonin, Muriel

    2016-01-01

    Pili produced by Lactococcus lactis subsp. lactis are putative linear structures consisting of repetitive subunits of the major pilin PilB that forms the backbone, pilin PilA situated at the distal end of the pilus, and an anchoring pilin PilC that tethers the pilus to the peptidoglycan. We determined the nanomechanical properties of pili using optical-tweezers force spectroscopy. Single pili were exposed to optical forces that yielded force-versus-extension spectra fitted using the Worm-Like Chain model. Native pili subjected to a force of 0–200 pN exhibit an inextensible, but highly flexible ultrastructure, reflected by their short persistence length. We tested a panel of derived strains to understand the functional role of the different pilins. First, we found that both the major pilin PilB and sortase C organize the backbone into a full-length organelle and dictate the nanomechanical properties of the pili. Second, we found that both PilA tip pilin and PilC anchoring pilin were not essential for the nanomechanical properties of pili. However, PilC maintains the pilus on the bacterial surface and may play a crucial role in the adhesion- and biofilm-forming properties of L. lactis. PMID:27010408

  20. Colloidal quantum dot lasers built on a passive two-dimensional photonic crystal backbone

    NASA Astrophysics Data System (ADS)

    Chang, Hojun; Min, Kyungtaek; Lee, Myungjae; Kang, Minsu; Park, Yeonsang; Cho, Kyung-Sang; Roh, Young-Geun; Woo Hwang, Sung; Jeon, Heonsu

    2016-03-01

    We report the room-temperature lasing action from two-dimensional photonic crystal (PC) structures composed of a passive Si3N4 backbone with an over-coat of CdSe/CdS/ZnS colloidal quantum dots (CQDs) for optical gain. When optically excited, devices lased in dual PC band-edge modes, with the modal dominance governed by the thickness of the CQD over-layer. The demonstrated laser platform should have an impact on future photonic integrated circuits as the on-chip coupling between active and passive components is readily achievable.We report the room-temperature lasing action from two-dimensional photonic crystal (PC) structures composed of a passive Si3N4 backbone with an over-coat of CdSe/CdS/ZnS colloidal quantum dots (CQDs) for optical gain. When optically excited, devices lased in dual PC band-edge modes, with the modal dominance governed by the thickness of the CQD over-layer. The demonstrated laser platform should have an impact on future photonic integrated circuits as the on-chip coupling between active and passive components is readily achievable. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08544f

  1. A backbone amide protecting group for overcoming difficult sequences and suppressing aspartimide formation.

    PubMed

    Abdel-Aal, Abu-Baker M; Papageorgiou, George; Raz, Richard; Quibell, Martin; Burlina, Fabienne; Offer, John

    2016-05-01

    A backbone amide bond protecting group, 2-hydroxy-4-methoxy-5-nitrobenzyl (Hmnb), improved the synthesis of aggregation and aspartimide-prone peptides. Introduction of Hmnb is automated and carried out during peptide assembly by addition of 4-methoxy-5-nitrosalicylaldehyde to the peptidyl-resin and on-resin reduction to the secondary amine. Acylation of the hindered secondary amine is aided by the formation of an internal nitrophenol ester that undergoes a favourable O,N intramolecular acyl transfer. This activated ester participates in the coupling and generally gives complete reaction with standard coupling conditions. Hmnb is easily available in a single preparative step from commercially available material. Different methods for removing the amide protecting group were explored. The protecting group is labile to acidolysis, following reduction of the nitro group to the aniline. The two main uses of backbone protection of preventing aspartimide formation and of overcoming difficult sequences are demonstrated, first with the synthesis of a challenging aspartimide-prone test sequence and then with the classic difficult sequence ACP (65-74) and a 23-mer homopolymer of polyalanine. PMID:27086749

  2. Supramolecular organization of the repetitive backbone unit of the Streptococcus pneumoniae pilus.

    PubMed

    Spraggon, Glen; Koesema, Eric; Scarselli, Maria; Malito, Enrico; Biagini, Massimiliano; Norais, Nathalie; Emolo, Carla; Barocchi, Michèle Anne; Giusti, Fabiola; Hilleringmann, Markus; Rappuoli, Rino; Lesley, Scott; Covacci, Antonello; Masignani, Vega; Ferlenghi, Ilaria

    2010-06-15

    Streptococcus pneumoniae, like many other Gram-positive bacteria, assembles long filamentous pili on their surface through which they adhere to host cells. Pneumococcal pili are formed by a backbone, consisting of the repetition of the major component RrgB, and two accessory proteins (RrgA and RrgC). Here we reconstruct by transmission electron microscopy and single particle image reconstruction method the three dimensional arrangement of two neighbouring RrgB molecules, which represent the minimal repetitive structural domain of the native pilus. The crystal structure of the D2-D4 domains of RrgB was solved at 1.6 A resolution. Rigid-body fitting of the X-ray coordinates into the electron density map enabled us to define the arrangement of the backbone subunits into the S. pneumoniae native pilus. The quantitative fitting provide evidence that the pneumococcal pilus consists uniquely of RrgB monomers assembled in a head-to-tail organization. The presence of short intra-subunit linker regions connecting neighbouring domains provides the molecular basis for the intrinsic pilus flexibility.

  3. Structure and assembly of group B streptococcus pilus 2b backbone protein.

    PubMed

    Cozzi, Roberta; Malito, Enrico; Lazzarin, Maddalena; Nuccitelli, Annalisa; Castagnetti, Andrea; Bottomley, Matthew J; Margarit, Immaculada; Maione, Domenico; Rinaudo, C Daniela

    2015-01-01

    Group B Streptococcus (GBS) is a major cause of invasive disease in infants. Like other Gram-positive bacteria, GBS uses a sortase C-catalyzed transpeptidation mechanism to generate cell surface pili from backbone and ancillary pilin precursor substrates. The three pilus types identified in GBS contain structural subunits that are highly immunogenic and are promising candidates for the development of a broadly-protective vaccine. Here we report the X-ray crystal structure of the backbone protein of pilus 2b (BP-2b) at 1.06Å resolution. The structure reveals a classical IgG-like fold typical of the pilin subunits of other Gram-positive bacteria. The crystallized portion of the protein (residues 185-468) encompasses domains D2 and D3 that together confer high stability to the protein due to the presence of an internal isopeptide bond within each domain. The D2+D3 region, lacking the N-terminal D1 domain, was as potent as the entire protein in conferring protection against GBS challenge in a well-established mouse model. By site-directed mutagenesis and complementation studies in GBS knock-out strains we identified the residues and motives essential for assembly of the BP-2b monomers into high-molecular weight complexes, thus providing new insights into pilus 2b polymerization.

  4. Supramolecular Organization of the Repetitive Backbone Unit of the Streptococcus pneumoniae Pilus

    PubMed Central

    Spraggon, Glen; Koesema, Eric; Scarselli, Maria; Malito, Enrico; Biagini, Massimiliano; Norais, Nathalie; Emolo, Carla; Barocchi, Michèle Anne; Giusti, Fabiola; Hilleringmann, Markus; Rappuoli, Rino; Lesley, Scott; Covacci, Antonello; Masignani, Vega; Ferlenghi, Ilaria

    2010-01-01

    Streptococcus pneumoniae, like many other Gram-positive bacteria, assembles long filamentous pili on their surface through which they adhere to host cells. Pneumococcal pili are formed by a backbone, consisting of the repetition of the major component RrgB, and two accessory proteins (RrgA and RrgC). Here we reconstruct by transmission electron microscopy and single particle image reconstruction method the three dimensional arrangement of two neighbouring RrgB molecules, which represent the minimal repetitive structural domain of the native pilus. The crystal structure of the D2-D4 domains of RrgB was solved at 1.6 Å resolution. Rigid-body fitting of the X-ray coordinates into the electron density map enabled us to define the arrangement of the backbone subunits into the S. pneumoniae native pilus. The quantitative fitting provide evidence that the pneumococcal pilus consists uniquely of RrgB monomers assembled in a head-to-tail organization. The presence of short intra-subunit linker regions connecting neighbouring domains provides the molecular basis for the intrinsic pilus flexibility. PMID:20559564

  5. Structure and Assembly of Group B Streptococcus Pilus 2b Backbone Protein

    PubMed Central

    Cozzi, Roberta; Malito, Enrico; Lazzarin, Maddalena; Nuccitelli, Annalisa; Castagnetti, Andrea; Bottomley, Matthew J.; Margarit, Immaculada; Maione, Domenico; Rinaudo, C. Daniela

    2015-01-01

    Group B Streptococcus (GBS) is a major cause of invasive disease in infants. Like other Gram-positive bacteria, GBS uses a sortase C-catalyzed transpeptidation mechanism to generate cell surface pili from backbone and ancillary pilin precursor substrates. The three pilus types identified in GBS contain structural subunits that are highly immunogenic and are promising candidates for the development of a broadly-protective vaccine. Here we report the X-ray crystal structure of the backbone protein of pilus 2b (BP-2b) at 1.06Å resolution. The structure reveals a classical IgG-like fold typical of the pilin subunits of other Gram-positive bacteria. The crystallized portion of the protein (residues 185-468) encompasses domains D2 and D3 that together confer high stability to the protein due to the presence of an internal isopeptide bond within each domain. The D2+D3 region, lacking the N-terminal D1 domain, was as potent as the entire protein in conferring protection against GBS challenge in a well-established mouse model. By site-directed mutagenesis and complementation studies in GBS knock-out strains we identified the residues and motives essential for assembly of the BP-2b monomers into high-molecular weight complexes, thus providing new insights into pilus 2b polymerization. PMID:25942637

  6. RNA-Redesign: a web server for fixed-backbone 3D design of RNA

    PubMed Central

    Yesselman, Joseph D.; Das, Rhiju

    2015-01-01

    RNA is rising in importance as a design medium for interrogating fundamental biology and for developing therapeutic and bioengineering applications. While there are several online servers for design of RNA secondary structure, there are no tools available for the rational design of 3D RNA structure. Here we present RNA-Redesign (http://rnaredesign.stanford.edu), an online 3D design tool for RNA. This resource utilizes fixed-backbone design to optimize the sequence identity and nucleobase conformations of an RNA to match a desired backbone, analogous to fundamental tools that underlie rational protein engineering. The resulting sequences suggest thermostabilizing mutations that can be experimentally verified. Further, sequence preferences that differ between natural and computationally designed sequences can suggest whether natural sequences possess functional constraints besides folding stability, such as cofactor binding or conformational switching. Finally, for biochemical studies, the designed sequences can suggest experimental tests of 3D models, including concomitant mutation of base triples. In addition to the designs generated, detailed graphical analysis is presented through an integrated and user-friendly environment. PMID:25964298

  7. Molecular basis for chloronium-mediated meroterpene cyclization: cloning, sequencing, and heterologous expression of the napyradiomycin biosynthetic gene cluster.

    PubMed

    Winter, Jaclyn M; Moffitt, Michelle C; Zazopoulos, Emmanuel; McAlpine, James B; Dorrestein, Pieter C; Moore, Bradley S

    2007-06-01

    Structural inspection of the bacterial meroterpenoid antibiotics belonging to the napyradiomycin family of chlorinated dihydroquinones suggests that the biosynthetic cyclization of their terpenoid subunits is initiated via a chloronium ion. The vanadium-dependent haloperoxidases that catalyze such reactions are distributed in fungi and marine algae and have yet to be characterized from bacteria. The cloning and sequence analysis of the 43-kb napyradiomycin biosynthetic cluster (nap) from Streptomyces aculeolatus NRRL 18422 and from the undescribed marine sediment-derived Streptomyces sp. CNQ-525 revealed 33 open reading frames, three of which putatively encode vanadium-dependent chloroperoxidases. Heterologous expression of the CNQ-525-based nap biosynthetic cluster in Streptomyces albus produced at least seven napyradiomycins, including the new analog 2-deschloro-2-hydroxy-A80915C. These data not only revealed the molecular basis behind the biosynthesis of these novel meroterpenoid natural products but also resulted in the first in vivo verification of vanadium-dependent haloperoxidases.

  8. A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles

    PubMed Central

    Liu, Yuan; Jacobs, Hollie K.

    2011-01-01

    N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized 5- and 6-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,β-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15. PMID:21499514

  9. Evolution of a short route to strychnine by using the samarium-diiodide-induced cascade cyclization as a key step.

    PubMed

    Beemelmanns, Christine; Reissig, Hans-Ulrich

    2015-06-01

    This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI2 allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI2 -induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.

  10. Oxygen switch in visible-light photoredox catalysis: radical additions and cyclizations and unexpected C-C-bond cleavage reactions.

    PubMed

    Zhu, Shaoqun; Das, Arindam; Bui, Lan; Zhou, Hanjun; Curran, Dennis P; Rueping, Magnus

    2013-02-01

    Visible light photoredox catalyzed inter- and intramolecular C-H functionalization reactions of tertiary amines have been developed. Oxygen was found to act as chemical switch to trigger two different reaction pathways and to obtain two different types of products from the same starting material. In the absence of oxygen, the intermolecular addition of N,N-dimethyl-anilines to electron-deficient alkenes provided γ-amino nitriles in good to high yields. In the presence of oxygen, a radical addition/cyclization reaction occurred which resulted in the formation of tetrahydroquinoline derivatives in good yields under mild reaction conditions. The intramolecular version of the radical addition led to the unexpected formation of indole-3-carboxaldehyde derivatives. Mechanistic investigations of this reaction cascade uncovered a new photoredox catalyzed C-C bond cleavage reaction.

  11. Synthesis of a Pentacene-Type Silaborin via Double Dehydrogenative Cyclization of 1,4-Diboryl-2,5-disilylbenzene.

    PubMed

    Hirofuji, Tatsuya; Ikeda, Toshiaki; Haino, Takeharu; Yamamoto, Yohsuke; Kawachi, Atsushi

    2016-07-01

    A new pentacene-type silaborin, in which three benzene rings are bridged by silicon and boron atoms, has been synthesized and characterized by using NMR spectroscopy and X-ray crystallographic analysis. The precursor, 1,4-bis(dimesitylboryl)-2,5-bis(phenylsilyl)benzene (4), was prepared by stepwise introduction of a silyl group and a boryl group to a benzene ring starting from 1,4-dibromobenzene. Double cyclization of 4 proceeds by a H-Mes exchange and a B-H/C-H dehydrogenative condensation to afford pentacene-type silaborin 5. X-ray crystal structure analysis reveals that 5 adopts a bent structure rather than a planar one. UV/Vis spectra and DFT calculations for 5 reveal a lowering of the LUMO energy level compared with corresponding anthracene-type 3. PMID:27273363

  12. Giffonins J-P, Highly Hydroxylated Cyclized Diarylheptanoids from the Leaves of Corylus avellana Cultivar "Tonda di Giffoni".

    PubMed

    Masullo, Milena; Cantone, Vincenza; Cerulli, Antonietta; Lauro, Gianluigi; Messano, Francesco; Russo, Gian Luigi; Pizza, Cosimo; Bifulco, Giuseppe; Piacente, Sonia

    2015-12-24

    Two new diaryl ether heptanoids, giffonins J and K (1 and 2), along with five new diarylheptanoids, giffonins L-P (3-7), were isolated from a methanol extract of the leaves of Corylus avellana cultivar "Tonda di Giffoni". These compounds were identified as highly hydroxylated cyclized diarylheptanoids by 1D- and 2D-NMR experiments. The relative configurations of giffonins J-P (1-7) were established by a combined QM (quantum mechanical)/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The cytotoxic activities of giffonins J-P (1-7) were evaluated against the human osteosarcoma U2Os and SAOs cell lines.

  13. Giffonins J-P, Highly Hydroxylated Cyclized Diarylheptanoids from the Leaves of Corylus avellana Cultivar "Tonda di Giffoni".

    PubMed

    Masullo, Milena; Cantone, Vincenza; Cerulli, Antonietta; Lauro, Gianluigi; Messano, Francesco; Russo, Gian Luigi; Pizza, Cosimo; Bifulco, Giuseppe; Piacente, Sonia

    2015-12-24

    Two new diaryl ether heptanoids, giffonins J and K (1 and 2), along with five new diarylheptanoids, giffonins L-P (3-7), were isolated from a methanol extract of the leaves of Corylus avellana cultivar "Tonda di Giffoni". These compounds were identified as highly hydroxylated cyclized diarylheptanoids by 1D- and 2D-NMR experiments. The relative configurations of giffonins J-P (1-7) were established by a combined QM (quantum mechanical)/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The cytotoxic activities of giffonins J-P (1-7) were evaluated against the human osteosarcoma U2Os and SAOs cell lines. PMID:26606246

  14. Direct photolysis of MeO-PBDEs in water and methanol: focusing on cyclization product MeO-PBDFs.

    PubMed

    Xue, Weifeng; Chen, Jingwen; Xie, Qing; Zhao, Hongxia

    2015-11-01

    Polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs can transform into polybrominated dibenzofurans (PBDFs) via photocyclization. However, it is unclear whether methoxylated PBDEs (MeO-PBDEs) can photocyclize to form MeO-PBDFs. In this study, 5-MeO-BDE-47, 5'-MeO-BDE-99 and 6-MeO-BDE-85 were selected as models to investigate their direct photolysis, especially photocyclization in two solvent environments (water and methanol) using simulated photochemical experiments and density functional theory (DFT) calculations. The experimental results showed that MeO-PBDEs had faster direct photolysis reactions and higher quantum yields in methanol, and MeO-PBDFs could only be formed in a methanol solution of 5-MeO-BDE-47. The DFT results indicated that the lowest excited triplet state MeO-PBDEs can form dibenzofurans via direct cyclization pathways. Intra-annular H-elimination was found to be the rate-determining step for most cyclization pathways with high reaction barriers (⩾19.7kcal/mol), while 5-MeO-BDE-47 was found to have a distinct pathway for which the rate-determining step is ring closure with a low barrier (13.8kcal/mol) in a methanol environment. For this pathway, H-elimination assisted by Br cleaved from an ortho-C-Br bond was observed with a 2.0kcal/mol barrier. Thus, the DFT results reasonably explained the experimental findings, and the photocyclization of MeO-PBDEs depended on the specific Br-substitution patterns and specific effects of the environmental media.

  15. Donor Properties of a New Class of Guanidinate Ligands Possessing Ketimine Backbones: A Comparative Study Using Iron.

    PubMed

    Maity, Arnab K; Metta-Magaña, Alejandro J; Fortier, Skye

    2015-10-19

    Addition of 1 equiv of LiN═C(t)Bu2 or LiN═Ad (Ad = 2-adamantyl) to the aryl carbodiimide C(NDipp)2 (Dipp = 2,6-diisopropylphenyl) readily generates the lithium ketimine-guanidinates Li(THF)2[(X)C(NDipp)2] (X = N═C(t)Bu2 (1-(t)Bu), N═Ad (1-Ad)) in excellent yields. These new ligands can be readily metalated with iron to give the N,N'-bidentate chelates [{(X)C(NDipp)2}FeBr]2 (X = N═C(t)Bu2 (5-(t)Bu), N═Ad (5-Ad)), in which the ketimines behave as noncoordinating backbone substituents. In an effort to understand the potential electronic contributions of the ketimine group to the ligand architecture, a thorough structural and electronic study was conducted comparing the features and properties of 5-(t)Bu and 5-Ad to their guanidinate and amidinate analogues [{(X)C(NDipp)2}FeBr]2 (X = (i)Pr2N (6), (t)Bu (7)). Solid-state structural analyses indicate little electronic contribution from the N-ketimine nitrogen atom, while solution-phase electronic absorption spectra of 5-(t)Bu and 5-Ad are qualitatively similar to the amidinate complex 7. Yet, electrochemical measurements do show the donor properties of the ketimine-guanidinate in 5-(t)Bu to be intermediate between its guanidinate and amidinate counterparts in 6 and 7. Preliminary reactivity studies also show that the reduction chemistry of 5-(t)Bu diverges significantly from that of 6 and 7. Treatment of 5-(t)Bu with excess magnesium or 1 equiv of KC8 leads to the formation of the Fe(I)-Fe(I) complex [{μ-((t)Bu2C═N)C(NDipp)2}2Fe2] (11), which possesses an exceedingly short Fe═Fe bond (2.1516(5) Å), while neither 6 nor 7 forms dinuclear complexes upon reduction. This result demonstrates that ketimine-guanidinates do not simply behave as amidinate variants but can contribute to distinctive metal chemistry of their own. PMID:26419613

  16. Tuning backbones and side-chains of cationic conjugated polymers for optical signal amplification of fluorescent DNA detection.

    PubMed

    Huang, Yan-Qin; Liu, Xing-Fen; Fan, Qu-Li; Wang, Lihua; Song, Shiping; Wang, Lian-Hui; Fan, Chunhai; Huang, Wei

    2009-06-15

    Three cationic conjugated polymers (CCPs) exhibiting different backbone geometries and charge densities were used to investigate how their conjugated backbone and side chain properties, together with the transitions of DNA amphiphilic properties, interplay in the CCP/DNA-C* (DNA-C*: fluorophore-labeled DNA) complexes to influence the optical signal amplification of fluorescent DNA detection based on Förster resonance energy transfer (FRET). By examining the FRET efficiencies to dsDNA-C* (dsDNA: double-stranded DNA) and ssDNA-C* (ssDNA: single-stranded DNA) for each CCP, twisted conjugated backbones and higher charge densities were proved to facilitate electrostatic attraction in CCP/dsDNA-C* complexes, and induced improved sensitivity to DNA hybridization. Especially, by using the CCP with twisted conjugated backbone and the highest charge density, a more than 7-fold higher efficiency of FRET to dsDNA-C* was found than to ssDNA-C*, indicating a high signal amplification for discriminating between dsDNA and ssDNA. By contrast, linear conjugated backbones and lower charge density were demonstrated to favor hydrophobic interactions in CCP/ssDNA-C* complexes. These findings provided guidelines for the design of novel sensitive CCP, which can be useful to recognize many other important DNA activities involving transitions of DNA amphiphilic properties like DNA hybridization, such as specific DNA binding with ions, some secondary or tertiary structural changes of DNA, and so forth.

  17. The Inherent Conformational Preferences of Glutamine-Containing Peptides: the Role for Side-Chain Backbone Hydrogen Bonds

    NASA Astrophysics Data System (ADS)

    Walsh, Patrick S.; McBurney, Carl; Gellman, Samuel H.; Zwier, Timothy S.

    2015-06-01

    Glutamine is widely known to be found in critical regions of peptides which readily fold into amyloid fibrils, the structures commonly associated with Alzheimer's disease and glutamine repeat diseases such as Huntington's disease. Building on previous single-conformation data on Gln-containing peptides containing an aromatic cap on the N-terminus (Z-Gln-OH and Z-Gln-NHMe), we present here single-conformation UV and IR spectra of Ac-Gln-NHBn and Ac-Ala-Gln-NHBn, with its C-terminal benzyl cap. These results point towards side-chain to backbone hydrogen bonds dominating the structures observed in the cold, isolated environment of a molecular beam. We have identified and assigned three main conformers for Ac-Gln-NHBn all involving primary side-chain to backbone interactions. Ac-Ala-Gln-NHBn extends the peptide chain by one amino acid, but affords an improvement in the conformational flexibility. Despite this increase in the flexibility, only a single conformation is observed in the gas-phase: a structure which makes use of both side-chain-to-backbone and backbone-to-backbone hydrogen bonds.

  18. Palladium-catalyzed synthesis of indoles via ammonia cross-coupling-alkyne cyclization.

    PubMed

    Alsabeh, Pamela G; Lundgren, Rylan J; Longobardi, Lauren E; Stradiotto, Mark

    2011-06-28

    The synthesis of indoles via the metal-catalyzed cross-coupling of ammonia is reported for the first time; the developed protocol also allows for the unprecedented use of methylamine or hydrazine as coupling partners. These Pd/Josiphos-catalyzed reactions proceed under relatively mild conditions for a range of 2-alkynylbromoarenes.

  19. Bromoallenes as allyl dication equivalents in the presence or absence of palladium(0): direct construction of bicyclic sulfamides containing five- to eight-membered rings by tandem cyclization of bromoallenes.

    PubMed

    Hamaguchi, Hisao; Kosaka, Shohei; Ohno, Hiroaki; Fujii, Nobutaka; Tanaka, Tetsuaki

    2007-01-01

    A highly regioselective synthesis of bicyclic sulfamides is described. Based on our recent discovery that bromoallenes can act as allyl dication equivalents in the presence of a palladium catalyst and alcohol, we investigated tandem cyclization of bromoallenes bearing a sulfamide group. It is found that some bromoallenes act as allyl dication equivalents even in the absence of a palladium(0) catalyst to afford cyclosulfamides containing five- or six-membered rings. While the palladium-free cyclization is dependent on the substrate structure affording the bicyclic sulfamides through the first cyclization onto the proximal or central carbon atom of the bromoallenes, the palladium-catalyzed reaction strongly promotes the first cyclization onto the central allenic carbon atom to afford bicyclic sulfamides containing a seven- or eight-membered ring. Formation of two types of bicyclic sulfamides from single bromoallenes by simply changing the reaction conditions is also described. PMID:17200916

  20. Polystannanes: processible molecular metals with defined chemical structures.

    PubMed

    Caseri, Walter

    2016-10-01

    Polystannanes are a unique class of materials as those inorganic polymers (more precisely organometallic polymers) appear to be hitherto the only characterized polymers with a backbone of covalently bound metal atoms. This review reflects the synthesis, spectroscopic characterization (in particular (119)Sn NMR and UV-vis spectroscopy), physical properties and material properties of polystannanes, and their processing into (oriented) films and fiber blends.

  1. Histidine-Directed Arylation/Alkenylation of Backbone N-H Bonds Mediated by Copper(II).

    PubMed

    Ohata, Jun; Minus, Matthew B; Abernathy, Morgan E; Ball, Zachary T

    2016-06-22

    Chemical modification of proteins and peptides represents a challenge of reaction design as well as an important biological tool. In contrast to side-chain modification, synthetic methods to alter backbone structure are extremely limited. In this communication, copper-mediated backbone N-alkenylation or N-arylation of peptides and proteins by direct modification of natural sequences is described. Histidine residues direct oxidative coupling of boronic acids at the backbone NH of a neighboring amino acid. The mild reaction conditions in common physiological buffers, at ambient temperature, are compatible with proteins and biological systems. This simple reaction demonstrates the potential for directed reactions in complex systems to allow modification of N-H bonds that directly affect polypeptide structure, stability, and function. PMID:27249339

  2. Effect of Nanoconfinement on the Glass Transition Temperature and Small Molecule Diffusion in Polymers of Varying Backbone Stiffness

    NASA Astrophysics Data System (ADS)

    Deng, Hui; Mundra, Manish; Torkelson, John

    2010-03-01

    Fluorescence spectroscopy was used to determine the glass transition temperature in ultrathin supported bisphenol-A polysulfone (BPAPS) and bisphenol-A polycarbonate (BPAPC) films and compared to previous results for ultrathin supported polystyrene (PS) films. BPAPC and BPAPS are more rigid than PS due to the presence of aromatic rings in their polymer backbones. A dramatic increase in Tg-reduction upon confinement was seen for polymers with increased backbone stiffness. A fluorescence-multilayer film technique was then used to determine the diffusion coefficient of a small molecule probe in ultrathin supported PS films. A decrease in the diffusion coefficient of the probe was observed upon confinement of the PS films. This procedure is also being applied to ultrathin supported BPAPC and BPAPS films to explore the impact of polymer backbone rigidity on small molecule diffusion in nanoconfined polymers.

  3. Gene families as soft cliques with backbones: Amborella contrasted with other flowering plants

    PubMed Central

    2014-01-01

    Background Chaining is a major problem in constructing gene families. Results We define a new kind of cluster on graphs with strong and weak edges: soft cliques with backbones (SCWiB). This differs from other definitions in how it controls the "chaining effect", by ensuring clusters satisfy a tolerant edge density criterion that takes into account cluster size. We implement algorithms for decomposing a graph of similarities into SCWiBs. We compare examples of output from SCWiB and the Markov Cluster Algorithm (MCL), and also compare some curated Arabidopsis thaliana gene families with the results of automatic clustering. We apply our method to 44 published angiosperm genomes with annotation, and discover that Amborella trichopoda is distinct from all the others in having substantially and systematically smaller proportions of moderate- and large-size gene families. Conclusions We offer several possible evolutionary explanations for this result. PMID:25572777

  4. The optimization issues in an agile all-photonic backbone network

    NASA Astrophysics Data System (ADS)

    Zhang, Yiming; Yang, Oliver W.; Zhai, Yihua

    2005-02-01

    The Agile All-photonic Backbone Network (AAPN) architecture has been proposed by the telecommunication industry as a potential candidate for the ultra high speed Next Generation Optical Network (NGON) architecture. AAPN network structure is composed of adaptive optical core switches and edge routers in an overlaid star physical topology. In this paper, we examine various optimization issues for AAPN architectures. The optimization procedure is based on a Lagrangean relaxation and subgradient method. Based on the optimization methodology provided in the previous research, we propose a modified algorithm to optimize AAPN networks, with respect to the assumptions used in AAPN. The results for different network configurations are studied and the influence of network resources is also studied. Our algorithm is shown to be very computational effective on the AAPN networks, and the bounds generated are mostly within 1% of the final objective value.

  5. X-shooter-backbone and UV-blue and visible spectrographs: final AIV and measured performances

    NASA Astrophysics Data System (ADS)

    Rasmussen, Per Kjærgaard; Zerbi, Filippo M.; Dekker, Hans; Vernet, Joel; Andersen, Jeppe J.; De Caprio, Vincenzo; Dimarcantonio, Paolo; D'Odorico, Sandro; Lizon, Jean-Louis; Lucuix, Christian; Michaelsen, Niels; Molinari, Emilio; Nørregaard, Preben; Riva, Alberto; Riva, Marco; Santin, Paolo; Sørensen, Anton N.; Spanò, Paolo; Wistisen, Dennis

    2008-07-01

    X-shooter is a wide band (U to K) intermediate resolution (4000-14000) single object three-arms spectrograph for the VLT. Currently in the last phase of integration, X-shooter will see the first light at ESO Paranal as the first of the VLT second generation instruments in the last quarter of 2008. We describe in this paper the final steps in the integration and testing phase of the central Backbone with its key functions (including the active flexure compensation mirrors) and of the two UV-Blue and Visible spectroscopic arms. We report on the stability results of the preslit optics and of the spectrographs and on the remarkable efficiency which is derived from the measurements of the optical components of the instrument.

  6. RosettaBackrub—a web server for flexible backbone protein structure modeling and design

    PubMed Central

    Lauck, Florian; Smith, Colin A.; Friedland, Gregory F.; Humphris, Elisabeth L.; Kortemme, Tanja

    2010-01-01

    The RosettaBackrub server (http://kortemmelab.ucsf.edu/backrub) implements the Backrub method, derived from observations of alternative conformations in high-resolution protein crystal structures, for flexible backbone protein modeling. Backrub modeling is applied to three related applications using the Rosetta program for structure prediction and design: (I) modeling of structures of point mutations, (II) generating protein conformational ensembles and designing sequences consistent with these conformations and (III) predicting tolerated sequences at protein–protein interfaces. The three protocols have been validated on experimental data. Starting from a user-provided single input protein structure in PDB format, the server generates near-native conformational ensembles. The predicted conformations and sequences can be used for different applications, such as to guide mutagenesis experiments, for ensemble-docking approaches or to generate sequence libraries for protein design. PMID:20462859

  7. Side chain and backbone contributions of Phe508 to CFTR folding

    SciTech Connect

    Thibodeau, Patrick H.; Brautigam, Chad A.; Machius, Mischa; Thomas, Philip J.

    2010-12-07

    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.

  8. Using halogen bonds to address the protein backbone: a systematic evaluation.

    PubMed

    Wilcken, Rainer; Zimmermann, Markus O; Lange, Andreas; Zahn, Stefan; Boeckler, Frank M

    2012-08-01

    Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipresent carbonyls of the protein backbone. We characterize energetics and directionality and elucidate their spatial variability in sub-optimal geometries that are expected to occur in protein-ligand complexes featuring a multitude of concomitant interactions. By deriving simple rules, we aid medicinal chemists and chemical biologists in easily exploiting them for scaffold decoration and design. Our work shows that carbonyl-halogen bonds may be used to expand the patentable medicinal chemistry space, redefining halogens as key features. Furthermore, this data will be useful for implementing halogen bonds into pharmacophore models or scoring functions making the QM information available for automatic molecular recognition in virtual high throughput screening.

  9. "Chameleonic" backbone hydrogen bonds in protein binding and as drug targets.

    PubMed

    Menéndez, C A; Accordino, S R; Gerbino, D C; Appignanesi, G A

    2015-10-01

    We carry out a time-averaged contact matrix study to reveal the existence of protein backbone hydrogen bonds (BHBs) whose net persistence in time differs markedly form their corresponding PDB-reported state. We term such interactions as "chameleonic" BHBs, CBHBs, precisely to account for their tendency to change the structural prescription of the PDB for the opposite bonding propensity in solution. We also find a significant enrichment of protein binding sites in CBHBs, relate them to local water exposure and analyze their behavior as ligand/drug targets. Thus, the dynamic analysis of hydrogen bond propensity might lay the foundations for new tools of interest in protein binding-site prediction and in lead optimization for drug design. PMID:26486885

  10. NMR Structure Determination for Larger Proteins Using Backbone-Only Data

    PubMed Central

    Raman, Srivatsan; Lange, Oliver F.; Rossi, Paolo; Tyka, Michael; Wang, Xu; Aramini, James; Liu, Gaohua; Ramelot, Theresa; Eletsky, Alexander; Szyperski, Thomas; Kennedy, Michael; Prestegard, James; Montelione, Gaetano T.; Baker, David

    2010-01-01

    Conventional protein structure determination from nuclear magnetic resonance data relies heavily on side-chain proton-proton distances. The necessary side-chain resonance assignment, however, is labor intensive and prone to error. Here we show that structures can be accurately determined without NMR information on the sidechains for proteins up to 25 kDa by incorporating backbone chemical shifts, residual dipolar couplings, and amide proton distances into the Rosetta protein structure modelling methodology. These data, which are too sparse for conventional methods, serve only to guide conformational search towards the lowest energy conformations in the folding landscape; the details of the computed models are determined by the physical chemistry implicit in the Rosetta all atom energy function. The new method is not hindered by the deuteration required to suppress nuclear relaxation processes for proteins greater than 15 kDa, and should enable routine NMR structure determination for larger proteins. PMID:20133520

  11. Modulation of Backbone Flexibility for Effective Dissociation of Antibacterial and Hemolytic Activity in Cyclic Peptides.

    PubMed

    Oddo, Alberto; Thomsen, Thomas T; Britt, Hannah M; Løbner-Olesen, Anders; Thulstrup, Peter W; Sanderson, John M; Hansen, Paul R

    2016-08-11

    Bacterial resistance to antibiotic therapy is on the rise and threatens to evolve into a worldwide emergency: alternative solutions to current therapies are urgently needed. Cationic amphipathic peptides are potent membrane-active agents that hold promise as the next-generation therapy for multidrug-resistant infections. The peptides' behavior upon encountering the bacterial cell wall is crucial, and much effort has been dedicated to the investigation and optimization of this amphipathicity-driven interaction. In this study we examined the interaction of a novel series of nine-membered flexible cyclic AMPs with liposomes mimicking the characteristics of bacterial membranes. Employed techniques included circular dichroism and marker release assays, as well as microbiological experiments. Our analysis was aimed at correlating ring flexibility with their antimicrobial, hemolytic, and membrane activity. By doing so, we obtained useful insights to guide the optimization of cyclic antimicrobial peptides via modulation of their backbone flexibility without loss of activity. PMID:27563396

  12. Insights on peptide backbone N-H acidity: Structure of anions, hydration effects

    NASA Astrophysics Data System (ADS)

    Oliva, Antoni; Henry, Bernard; Ruiz-López, Manuel F.

    2013-03-01

    Despite the key role played by deamidation reactions in biochemical phenomena such as aging processes, knowledge of factors determining peptide backbone N-H acidities is scarce. We report a theoretical study on this topic by means of quantum-chemical calculations. Gas-phase acidities and pKa's in water have been estimated. The results agree reasonably well with available experimental data. Further analysis suggests that the secondary peptide structure, in addition to hydration effects, is the main factor determining pKa. In particular, we predict N-H protons to be more acidic in β-turns than in α-helices, a finding that may have broad biological implications.

  13. Novel Natural Oximes and Oxime Esters with a Vibralactone Backbone from the Basidiomycete Boreostereum vibrans

    PubMed Central

    Chen, He‐Ping; Zhao, Zhen‐Zhu; Li, Zheng‐Hui; Dong, Ze‐Jun; Wei, Kun; Bai, Xue; Zhang, Ling; Wen, Chun‐Nan

    2016-01-01

    Abstract A variety of novel natural products with significant bioactivities are produced by the basidiomycete Boreostereum vibrans. In the present study, we describe 16 novel natural oximes and oxime esters with a vibralactone backbone, vibralactoximes, which were isolated from the scale‐up fermentation broth of B. vibrans. Their structures were determined through extensive spectroscopic analyses. These compounds represent the first oxime esters from nature. The hypothetical biosynthetic pathway of these compounds was also proposed. Seven compounds exhibited significant pancreatic lipase inhibitory activity, while ten compounds exhibited cytotoxicities against five human cancer cell lines (HL‐60, SMMC‐7721, A‐549, MCF‐7, and SW480), with IC50 values comparable with those of cisplatin. PMID:27308232

  14. The Effects of NHC-Backbone Substitution on Efficiency in Ruthenium-based Olefin Metathesis

    PubMed Central

    Kuhn, Kevin M.; Bourg, Jean-Baptiste; Chung, Cheol K.; Virgil, Scott C.; Grubbs, Robert H.

    2009-01-01

    A series of ruthenium olefin metathesis catalysts bearing N-heterocyclic carbene (NHC) ligands with varying degrees of backbone and N-aryl substitution have been prepared. These complexes show greater resistance to decomposition through C–H activation of the N-aryl group, resulting in increased catalyst lifetimes. This work has utilized robotic technology to examine the activity and stability of each catalyst in metathesis, providing insights into the relationship between ligand architecture and enhanced efficiency. The development of this robotic methodology has also shown that, under optimized conditions, catalyst loadings as low as 25 ppm can lead to 100% conversion in the ring-closing metathesis of diethyl diallylmalonate. PMID:19351207

  15. Increased Diels-Alderase activity through backbone remodeling guided by Foldit players.

    PubMed

    Eiben, Christopher B; Siegel, Justin B; Bale, Jacob B; Cooper, Seth; Khatib, Firas; Shen, Betty W; Players, Foldit; Stoddard, Barry L; Popovic, Zoran; Baker, David

    2012-02-01

    Computational enzyme design holds promise for the production of renewable fuels, drugs and chemicals. De novo enzyme design has generated catalysts for several reactions, but with lower catalytic efficiencies than naturally occurring enzymes. Here we report the use of game-driven crowdsourcing to enhance the activity of a computationally designed enzyme through the functional remodeling of its structure. Players of the online game Foldit were challenged to remodel the backbone of a computationally designed bimolecular Diels-Alderase to enable additional interactions with substrates. Several iterations of design and characterization generated a 24-residue helix-turn-helix motif, including a 13-residue insertion, that increased enzyme activity >18-fold. X-ray crystallography showed that the large insertion adopts a helix-turn-helix structure positioned as in the Foldit model. These results demonstrate that human creativity can extend beyond the macroscopic challenges encountered in everyday life to molecular-scale design problems. PMID:22267011

  16. On the photostability of peptides after selective photoexcitation of the backbone: prompt versus slow dissociation.

    PubMed

    Byskov, Camilla Skinnerup; Jensen, Frank; Jørgensen, Thomas J D; Nielsen, Steen Brøndsted

    2014-08-14

    Vulnerability of biomolecules to ultraviolet radiation is intimately linked to deexcitation pathways: photostability requires fast internal conversion to the electronic ground state, but also intramolecular vibrational redistribution and cooling on a time scale faster than dissociation. Here we present a protocol to disentangle slow and non-hazardous statistical dissociation from prompt cleavage of peptide bonds by 210 nm light based on experiments on protonated peptides isolated in vacuo and tagged by 18-crown-6 ether (CE). The weakest link in the system is between the charged site and CE, which is remote from the initial site of excitation. Hence loss of CE serves as direct proof that energy has reached the charge-site end, leaving the backbone intact. Our work demonstrates that excitation of tertiary amide moieties (proline linkages) results in both prompt dissociation and statistical dissociation after energy randomisation over all vibrational degrees of freedom. PMID:24945849

  17. A recombinant, chimeric tetravalent dengue vaccine candidate based on a dengue virus serotype 2 backbone.

    PubMed

    Osorio, Jorge E; Wallace, Derek; Stinchcomb, Dan T

    2016-01-01

    Dengue fever is caused by infection with one of four dengue virus (DENV) serotypes (DENV-1-4), necessitating tetravalent dengue vaccines that can induce protection against all four DENV. Takeda's live attenuated tetravalent dengue vaccine candidate (TDV) comprises an attenuated DENV-2 strain plus chimeric viruses containing the prM and E genes of DENV-1, -3 and -4 cloned into the attenuated DENV-2 'backbone'. In Phase 1 and 2 studies, TDV was well tolerated by children and adults aged 1.5-45 years, irrespective of prior dengue exposure; mild injection-site symptoms were the most common adverse events. TDV induced neutralizing antibody responses and seroconversion to all four DENV as well as cross-reactive T cell-mediated responses that may be necessary for broad protection against dengue fever.

  18. Proton NMR assignments and regular backbone structure of bovine pancreatic ribonuclease A in aqueous solution

    SciTech Connect

    Robertson, A.D. ); Purisima, E.O. Cornell Univ., Ithaca, NY ); Eastman, M.A.; Scheraga, H.A. )

    1989-07-11

    Proton NMR assignments have been made for 121 of the 124 residues of bovine pancreatic ribonuclease A (RNase A). During the first stage of assignment, COSY and relayed COSY data were used to identify 40 amino acid spin systems belonging to alanine, valine, threonine, isoleucine, and serine residues. Approximately 60 other NH-{alpha}CH-{beta}CH systems were also identified but not assigned to specific amino acid type. NOESY data then were used to connect sequentially neighboring spin systems; approximately 475 of the possible 700 resonances in RNase A were assigned in this way. The authors' assignments agree with those for 20 residues assigned previously. NOESY correlations were used to identify regular backbone structure elements in RNase A, which are very similar to those observed in X-ray crystallographic studies.

  19. An effective approach for alleviating cation-induced backbone degradation in aromatic ether-based alkaline polymer electrolytes.

    PubMed

    Han, Juanjuan; Liu, Qiong; Li, Xueqi; Pan, Jing; Wei, Ling; Wu, Ying; Peng, Hanqing; Wang, Ying; Li, Guangwei; Chen, Chen; Xiao, Li; Lu, Juntao; Zhuang, Lin

    2015-02-01

    Aromatic ether-based alkaline polymer electrolytes (APEs) are one of the most popular types of APEs being used in fuel cells. However, recent studies have demonstrated that upon being grafted by proximal cations some polar groups in the backbone of such APEs can be attacked by OH(-), leading to backbone degradation in an alkaline environment. To resolve this issue, we performed a systematic study on six APEs. We first replaced the polysulfone (PS) backbone with polyphenylsulfone (PPSU) and polyphenylether (PPO), whose molecular structures contain fewer polar groups. Although improved stability was seen after this change, cation-induced degradation was still obvious. Thus, our second move was to replace the ordinary quaternary ammonia (QA) cation, which had been closely attached to the polymer backbone, with a pendant-type QA (pQA), which was linked to the backbone through a long side chain. After a stability test in a 1 mol/L KOH solution at 80 °C for 30 days, all pQA-type APEs (pQAPS, pQAPPSU, and pQAPPO) exhibited as low as 8 wt % weight loss, which is close to the level of the bare backbone (5 wt %) and remarkably lower than those of the QA-type APEs (QAPS, QAPPSU, and QAPPO), whose weight losses under the same conditions were >30%. The pQA-type APEs also possessed clear microphase segregation morphology, which led to ionic conductivities that were higher, and water uptakes and degrees of membrane swelling that were lower, than those of the QA-type APEs. These observations unambiguously indicate that designing pendant-type cations is an effective approach to increasing the chemical stability of aromatic ether-based APEs.

  20. An effective approach for alleviating cation-induced backbone degradation in aromatic ether-based alkaline polymer electrolytes.

    PubMed

    Han, Juanjuan; Liu, Qiong; Li, Xueqi; Pan, Jing; Wei, Ling; Wu, Ying; Peng, Hanqing; Wang, Ying; Li, Guangwei; Chen, Chen; Xiao, Li; Lu, Juntao; Zhuang, Lin

    2015-02-01

    Aromatic ether-based alkaline polymer electrolytes (APEs) are one of the most popular types of APEs being used in fuel cells. However, recent studies have demonstrated that upon being grafted by proximal cations some polar groups in the backbone of such APEs can be attacked by OH(-), leading to backbone degradation in an alkaline environment. To resolve this issue, we performed a systematic study on six APEs. We first replaced the polysulfone (PS) backbone with polyphenylsulfone (PPSU) and polyphenylether (PPO), whose molecular structures contain fewer polar groups. Although improved stability was seen after this change, cation-induced degradation was still obvious. Thus, our second move was to replace the ordinary quaternary ammonia (QA) cation, which had been closely attached to the polymer backbone, with a pendant-type QA (pQA), which was linked to the backbone through a long side chain. After a stability test in a 1 mol/L KOH solution at 80 °C for 30 days, all pQA-type APEs (pQAPS, pQAPPSU, and pQAPPO) exhibited as low as 8 wt % weight loss, which is close to the level of the bare backbone (5 wt %) and remarkably lower than those of the QA-type APEs (QAPS, QAPPSU, and QAPPO), whose weight losses under the same conditions were >30%. The pQA-type APEs also possessed clear microphase segregation morphology, which led to ionic conductivities that were higher, and water uptakes and degrees of membrane swelling that were lower, than those of the QA-type APEs. These observations unambiguously indicate that designing pendant-type cations is an effective approach to increasing the chemical stability of aromatic ether-based APEs. PMID:25594224