But can we make it work in water? Chemists are now exploring the design of molecular architectures that extend beyond covalent bonding. Taking inspiration from Nature, molecules that fold or self-assemble are being designed from first principles. Creating molecular systems that fold and assemble in water is currently a major challenge, although once created, such systems will be able to interact with biological structures and molecules in unprecedented ways. Our early foldamer studies verified that aromatic donor-acceptor interactions can be used as a remarkably strong stabilizing interaction in water, producing folded, stacked structures (Lokey and Iverson, Nature, 1995, 375, 303-5.) called aedamers. More recently, we have made the exciting discovery that chains of electron rich aromatic units will specifically recognize a complementary chain of electron deficient aromatic units in aqueous solution to form a stable duplex (Gabriel and Iverson, J. of the Am. Chem. Soc., 2002, 124, 15174-15175.). The first two specific aims of this proposal describe the creation and characterization of novel folding and assembling molecular systems that in water exploit the stabilizing and recognition abilities of the electron rich 1,5-dialkoxynaphthalene (DAN) and the electron deficient 1,4,5,8-naphthalene tetracarboxylic diimide (NDI) aromatic moieties. The last three specific aims take the next critical step and probe different interaction strategies with biological molecules. ? ? Spanning the range from basic science to practical application, we will 1) investigate an entirely new aedamer folding topology analogous to nucleic acid hairpins, 2) use the recognition ability of the DAN-NDI interaction to produce large molecular assemblies from smaller folding pieces, 3) investigate the utility of DAN-NDI interactions as a stabilizing force in a protein hydrophobic core, 4) create next-generation threading DNA poly-intercalators based on structures derived from NMR analysis of our NDI-based oligomers, and 5) use phage display to isolate a peptide with high affinity and specificity for binding a chain of NDI residues for potential use in biomedical and biotechnological applications. ? ?

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National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Basavappa, Ravi
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University of Texas Austin
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Ikkanda, B A; Iverson, B L (2016) Exploiting the interactions of aromatic units for folding and assembly in aqueous environments. Chem Commun (Camb) 52:7752-9
Peebles, Cameron; Alvey, Paul M; Lynch, Vincent et al. (2014) Time-Dependent Solid State Polymorphism of a Series of Donor-Acceptor Dyads. Cryst Growth Des 14:290-299
Ikkanda, Brian A; Samuel, Stevan A; Iverson, Brent L (2014) NDI and DAN DNA: nucleic acid-directed assembly of NDI and DAN. J Org Chem 79:2029-37
Peebles, Cameron; Piland, Rebecca; Iverson, Brent L (2013) More than meets the eye: conformational switching of a stacked dialkoxynaphthalene-naphthalenetetracarboxylic diimide (DAN-NDI) foldamer to an NDI-NDI fibril aggregate. Chemistry 19:11598-602
Rhoden Smith, Amy; Iverson, Brent L (2013) Threading polyintercalators with extremely slow dissociation rates and extended DNA binding sites. J Am Chem Soc 135:12783-9
Smith, Amy Rhoden; Ikkanda, Brian A; Holman, Garen G et al. (2012) Subtle recognition of 14-base pair DNA sequences via threading polyintercalation. Biochemistry 51:4445-52
Holman, Garen G; Zewail-Foote, Maha; Smith, Amy Rhoden et al. (2011) A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant. Nat Chem 3:875-81
Alvey, Paul M; Reczek, Joseph J; Lynch, Vincent et al. (2010) A systematic study of thermochromic aromatic donor-acceptor materials. J Org Chem 75:7682-90
Chu, Yongjun; Hoffman, David W; Iverson, Brent L (2009) A pseudocatenane structure formed between DNA and A cyclic bisintercalator. J Am Chem Soc 131:3499-508
Bradford, Valerie J; Iverson, Brent L (2008) Amyloid-like behavior in abiotic, amphiphilic foldamers. J Am Chem Soc 130:1517-24

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