Browsing by Subject "Hydrogen bonding"

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Biochemical studies of spermidine/spermine N¹-acetyltransferase, an important regulator of cellular polyamines
(2008-08) Montemayor, Eric John, 1979-; Hoffman, David W., Ph. D.
The polyamines spermine and spermidine play important roles in many cellular processes, and unusual levels of these polyamines have been associated with numerous human diseases. Spermidine/spermine N¹-acetyltransferase (SSAT) is an enzyme involved in polyamine regulation, where acetylation of polyamines by SSAT ultimately leads to their degradation or export from the cell. In this dissertation, x-ray crystallography and nuclear magnetic resonance (NMR) are used to provide insights into the structure and function of this important enzyme. X-ray crystallography provided two distinct views of SSAT: one of the enzyme in complex with coenzyme A (CoA), and another of the enzyme in complex with CoA and the polyamine spermine. Together, the two structures reveal structural plasticity in the active site of the enzyme. The complex with spermine provides a direct view of polyamine binding by SSAT, and shows that the enzyme relies heavily on associated water molecules to bind spermine; these water molecules also appear to form a "proton relay" between the primary amine of spermine and the side-chain of a conserved glutamate residue. Guided by the structural results, NMR methods were used to test hypotheses regarding the enzyme mechanism of SSAT. The activity of the enzyme over a range of solution conditions, and towards different polyamine substrates, was determined; the effects of mutating single amino acids in the enzyme were also evaluated. The enzyme appeared to be most active between pH 8.5 and 9.5, and mutation of the aforementioned glutamate significantly altered this behavior. This suggests the glutamate is directly involved in the acetyltransfer reaction, where it likely functions as a catalytic base though the proton relay in the enzyme active site. These studies advance our general understanding of how polyamines are regulated in mammalian cells, and have the potential to assist in developing new therapeutic options for human diseases involving polyamines.
Effects of nanoconfinement on structure and properties of side-chain liquid crystalline polymers
(2013-12) Gonzalez Garza, Paola Anaid; Ellison, Christopher J.
Semi-crystalline polymers have shown increased crystalline order and size when confined in multilayered films by coextrusion1. The resulting large crystals lead to dramatic improvements in gas barrier properties. Ordered polymers whose characteristics are between that of the liquid phase and the crystalline phase are known as liquid crystalline polymers. The highly ordered mesogens in liquid crystalline polymers contribute to their exceptional bulk properties. In this research, side-chain liquid crystalline polymers were confined in multilayered films, made by either multilayer coextrusion or spin coating, with a non-liquid crystalline polymer in an attempt to improve the ordering of the liquid crystalline mesogens. The liquid crystalline behavior and morphology was studied to understand the correlation between the confinement size and the properties of the multilayer films. Commercial main chain liquid crystalline polymers and hydrogen bonded liquid crystalline polymers were also explored in this research for their use in multilayer coextrusion.
H-bond directed self-assembly of oligomeric molecular strands and hydrogen mediated rhodium-catalyzed reductive cyclization of 1,6-enynes
(2005) Gong, Hegui; Krische, Michael J.
Key structural and interactional features of the components for hydrogen bond mediated self-assembly are reviewed, with emphasis on the assembly of synthetic oligomers to form duplexes and tubular structures, as well as related applications in the design of functional materials. A strategy for the preparation of molecular strands that self-assemble through the action of interstrand H-bonds to form duplex superstructures is described. Specifically, duplex oligomers based on the 3,6-diaminopyridazine hydrogen-bonding motif were designed and prepared. The mode of assembly and the thermodynamic parameters of duplex aggregation are established by X-ray crystallographic analysis, 1 H NMR dilution experiments, isothermal titration calorimetry (ITC) and vapor pressure osmometry (VPO). ITC analysis indicates a strong positive cooperative effect upon strand extension from monomer to trimer. In addition, studies toward the design of molecular strands that assemble to form tubular structures are described. Here, alkyl chains decorated with aminopyrazolone moieties were examined. In the solid state, aminopyrazolones aggregate to form either linear H-bonded tapes or discrete cyclic tetramers, as established by single crystal X-ray diffraction analysis. Evidence for cyclic aggregation in solution, though not conclusive, led us to investigate bis(aminopyrazolone) systems, whereby the energy bias between the linear and cyclic aggregation modes could potentially be magnified to favor the latter. However, single crystal X-ray diffraction analysis of S,S-dihexylpropyl bis(aminopyrazolone) reveals a double H-bonded tape. The mode of assembly in solution for the bis(aminopyrazolone) could not be established unambiguously. Finally, the use of elemental hydrogen as a terminal reductant in the rhodiumcatalyzed enantioselective reductive cyclization of 1,6-enynes is described. Whereas 1,6- enynes containing 1,2-substituted alkenes fail to provide reductive cyclization products due to competitive cycloisomerization, related alkenes in the form of conjugated enones afford reductive cyclization products in good to excellent yield and enantioselection.
Phase and conformational behavior of LCST-driven stimuli responsive polymers
(2009-12) Simmons, David Samuel; Sanchez, Isaac C., 1941-
Several analytical mean field models are presented for the class of stimuli responsive polymers that are driven by the lower critical solution temperature (LCST) transition. For solutions above the polymer crossover concentration, a hybrid model combines lattice-fluid excluded volume and van-der-Waals interactions with a combinatorial approach for the statistics of hydrogen bonding, hydration, and ionic bonding. This approach yields models for the LCST of both neutral polymers and lightly charged polyelectrolytes in aqueous salt solution. The results are shown to be in semi-quantitative agreement with experimental data for the cloud point of polyethylene oxide (PEO) in aqueous solution with various salts, and some aspects of the lyotropic series are reproduced. Results for lightly charged polyelectrolytes are compared to and shown to be in qualitative agreement with aspects of experimentally observed behavior. Finally, a framework is established for extension of these models to further aspects of the lyotropic series and polyelectrolyte behavior. At the nanoscale, lattice fluid (LF) and scaled particle theory (SPT) approaches are employed to model the LCST-related coil-globule-transition (CGT) of isolated polymer chains in highly dilute solution. The predicted CGT behavior semi-quantitatively correlates with experimental results for several polymer-solvent systems and over a range of pressures. Both the LF and SPT models exhibit a heating induced coil-to-globule transition (HCGT) temperature that increases with pressure until it merges with a cooling induced coil-to-globule transition (CCGT). The point at which the CCGT and HCGT meet is a hypercritical point that also corresponds to a merging of the lower critical and upper critical solution temperatures. Theoretical results are discussed in terms of a generalized polymer/solvent phase diagram that possesses three hypercritical points. Within the lattice model, a dimensionless transition temperature [author gives mathematical symbol] is given for a long chain simply by the equation [author gives mathematical equation], where [part of the equation] is the bulk solvent occupied volume fraction at the transition temperature. Furthermore, there is a critical value of the ratio of polymer to solvent S-L characteristic temperature below which no HCGT transition is predicted for an infinite chain.
Utilization of nucleobase pairing to develop supramolecular polymers, electron transfer systems, and interaction with biological molecules
(2010-05) Lawrence, Candace Michelle; Sessler, Jonathan L.; Bielawski, Christopher W.; Magnus, Philip D.; Ellington, Andrew D.; Kerwin, Sean M.
Hydrogen bonding is seen extensively in Nature. It is manifest in DNA/RNA nucleic acid (nucleobase) pairing, the defining feature of the double helix, as well as in secondary structures in protein folding such as hairpin loops. This importance, thus coupled with the aesthetic appeal of nucleobase hydrogen-bonding interactions, has inspired us to design and synthesize new hydrogen-bonded assemblies that make use of Watson-Crick and Hoogsteen interactions. Currently, novel supramolecular architectures are being developed for the formation of supramolecular polymers via Watson-Crick hydrogen bonding of guanosine and cytidine. Supramolecular polymer formation occurs through hydrogen bonding, electronic interactions, and metal chelation, and allows for a highly thermodynamic system that can easily be broken and reformed through external stimuli. By synthesizing linear, metal-nucleobase, and functionalized guanosine entities, a variety of new “monomers” have been obtained. Their use in construction of main chain and side chain polymers, and G-quartet hydrogels are now being explored. The hydrogen bonding motifs used to develop supramolecular polymers are also attractive for developing through bond electron transfer systems. One inspiration for developing artificial donor-acceptor systems (i.e., linked through non-covalent interactions) comes from the light harvesting systems found in Nature. Triggered by a pulse of UV light, electron transfer across bridges, including charge separation and charge recombination processes can occur and the rates can be determined. As one part of this study, collaborators Igor Rubtsov and David Beratan studied how perturbing the vibrational modes of the bridge via IR pulse excitation, affected electron transfer. Mid-IR excitation of the donor-acceptor systems slowed the rate of electron transfer, likely because the molecular vibrations either disrupted the bridging hydrogen bonds or distorted the electronic interactions of the bridge. This observance could lend itself to the possibility of designing IR-controlled molecular switches and other devices Another mode of hydrogen bonding, Hoogsteen interactions, was explored in the context of developing a guanosine-quadruplex binder. Specifically, a pyrrole-based inosine was designed to direct hydrogen bonding via an extended Hoogsteen interaction in order to bind to quadruplex DNA. Quadruplex DNA has been studied as a folded form of DNA and, if stabilized, can inhibit gene replication especially amongst cancer strands. In summary, the candidate’s research efforts have focused on exploiting hydrogen bonding in nucleobases to construct novel supramolecular assemblies that could see eventual applications in materials chemistry, nanotechnology, and gene therapy.