Folding Topologies

We have employed aromatic donor-acceptor interactions between the electron-rich 1,5-dialkoxy naphthalene (Dan and electron-poor 1,4,5,8-naphthalene-tetracarboxylic diimide (Ndi) modular units in the past to program both inter-and intramolecular folding and assembly. Solid-phase peptide synthetic methods in concert with native chemical ligation are used to constrain non-alternating sequences of Dan and Ndi into cyclic molecules intended to adopt a hairpin-like folding topology as shown below. For example, a trimer of linked Dan-Dan-Ndi units was synthesized and cyclized such that the Ndi intercalates between the Dan units in the cyclic structure. We are currently characterizing the structures and properties of the molecules.

Amyloid-Like Conformational Switching of Donor-Acceptor Foldamers

We have designed an alternating foldamer that forms a pleated, stacked structure when placed in aqueous buffers by alternating electron-poor Ndi and electron-rich Dan units. The units are linked together using amino acid residues. By utilizing alternating hydrophobic and aspartic acid residues, we have achieved an amphiphilic, folded and pleated structure. After heating, these molecules form a well-ordered, irreversible hydrogel with a cross-linked fibrillar structure as shown by rhelogy , circular dichroism, and SEM studies. The thermodynamic and kinetic landscape of the hydrogelation process of these molecules mirrors that of amyloid proteins and polypeptides.

Enhancement of oligomer complexation through conformational preorganization

The utility of electronic donor-acceptor interactions as a motif for directed molecular assembly in aqueous environments has been extensively explored within the Iverson group. Early work involved the use of oligomers of electron deficient 1,4,5,8-naphthalenetetracarboxylic diimide (Ndi) units and electron rich 1,5-dialkoxynaphthalene (Dan) units tethered by aspartic acid residues. Initial investigations into the Dan-Ndi intermolecular association found that while the binding affinity of the hetero-duplex was relatively high, the formation of this complex was forced to compete with concurrent offset self-stacking between the Ndi units within individual oligomeric strands3. This lack of preorganization was thought to be aided by the high degree of flexibility inherent within the aspartic acid tether. The goal of this project is to introduce rigidity within the oligomer backbone to reduce the flexibility hopefully leading to an increase in the binding affinity of the hetero-duplex.
Two key concepts identified as being critical to successful linker design were the rigidification of the oligomer backbone as well as its ability to be solvated in an aqueous environment. Computer modeling of potential linkers indicated that the optimal distance between monomer units within the dimer was 7Å, since this afforded the requisite 3.5Å distance for aromatic donor-acceptor interactions. Recent literature has described the design and synthesis of a rigid proline-based molecular scaffold, exhibiting marked aqueous solubility, where the inflexibility of the molecule is conferred through the incorporation of two diketopiperazine rings4. Integration of this scaffold into the construction of Dan and Ndi dimers will enable a greater degree of preorganization of individual dimers resulting in an increased binding affinity upon hetero-duplex complexation. Complete optimization of the associative properties of Dan-Ndi interactions in water will provide the opportunity for the design of novel, more complex polymeric and oligomeric structures.