13 research outputs found

    Mix and match recognition modules for the formation of H-bonded duplexes.

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    Oligomeric molecules equipped with complementary H-bond recognition sites form stable duplexes in non-polar solvents. The use of a single H-bond between a good H-bond donor and a good H-bond acceptor as the recognition motif appended to a non-polar backbone leads to an architecture with interchangeable recognition alphabets. The interactions of three different families of H-bond acceptor oligomers (pyridine, pyridine N-oxide or phosphine oxide recognition module) with a family of H-bond donor oligomers (phenol recognition module) are compared. All three donor-acceptor combinations form stable duplexes, where the stability of the 1 : 1 complex increases with increasing numbers of recognition modules. The effective molarity for formation of intramolecular H-bonds that lead to zipping up of the duplex (EM) increases with decreasing flexibility of the recognition modules: 14 mM for the phosphine oxides which are connected to the backbone via a flexible linker; 40 mM for the pyridine N-oxides which have three fewer degrees of torsional freedom, and 80 mM for the pyridines where the geometry of the H-bond is more directional. However, the pyridine-phenol H-bond is an order of magnitude weaker than the other two types of H-bond, so overall the pyridine N-oxides form the most stable duplexes with the highest degree of cooperativity. The results show that it is possible to use different recognition motifs with the same duplex architecture, and this makes it possible to tune overall stabilities of the complexes by varying the components.We thank the EPSRC and ERC for fundin

    H-Bond Self-Assembly: Folding versus Duplex Formation

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    Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1-2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.We thank the Engineering and Physical Sciences Research Council (EP/J008044/2) and European Research Council (ERC-2012-AdG 320539-duplex) for funding

    Mix and match backbones for the formation of H-bonded duplexes.

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    The formation of well-defined supramolecular assemblies involves competition between intermolecular and intramolecular interactions, which is quantified by effective molarity. Formation of a duplex between two oligomers equipped with recognition sites displayed along a non-interacting backbone requires that once one intermolecular interaction has been formed, all subsequent interactions take place in an intramolecular sense. The efficiency of this process is governed by the geometric complementarity and conformational flexibility of the backbone linking the recognition sites. Here we report a series of phosphine oxide H-bond acceptor AA 2-mers and phenol H-bond donor DD 2-mers, where the two recognition sites are connected by isomeric backbone modules that vary in geometry and flexibility. All AA and DD combinations form stable AA·DD duplexes, where two cooperative H-bonds lead to an increase in stability of an order of magnitude compared with the corresponding A·D complexes that can only form one H-bond. For all six possible backbone combinations, the effective molarity for duplex formation is approximately constant (7-20 mM). Thus strict complementarity and high degrees of preorganisation are not required for efficient supramolecular assembly. Provided there is some flexibility, quite different backbone modules can be used interchangeably to construct stable H-bonded duplexes.We thank the EPSRC and ERC for funding.This is the final version of the article. It was first available from Royal Society of Chemistry via http://dx.doi.org/10.1039/C5SC04467

    c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3

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    Suppressor of cytokine signalling (SOCS) proteins are critical attenuators of cytokine-mediated signalling in diverse tissues. To determine the importance of Socs3 in mammary development, we generated mice in which Socs3 was deleted in mammary epithelial cells. No overt phenotype was evident during pregnancy and lactation, indicating that Socs3 is not a key physiological regulator of prolactin signalling. However, Socs3-deficient mammary glands exhibited a profound increase in epithelial apoptosis and tissue remodelling, resulting in precocious involution. This phenotype was accompanied by augmented Stat3 activation and a marked increase in the level of c-myc. Moreover, induction of c-myc before weaning using an inducible transgenic model recapitulated the Socs3 phenotype, and elevated expression of likely c-myc target genes, E2F-1, Bax and p53, was observed. Our data establish Socs3 as a critical attenuator of pro-apoptotic pathways that act in the developing mammary gland and provide evidence that c-myc regulates apoptosis during involution
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