Exploiting aromatic donor-acceptor recognition in the folding and binding of naphthyl oligomers

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Gabriel, Gregory John

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Biomolecules, for example, DNA and enzymes, perform nearly all the chemical processes essential for life. Their functions are dependent though on their ability to fold and bind into precise three-dimensional conformations and assemblies. A variety of oligomers that adopt compact conformations in solution, termed foldamers, have been synthesized to elucidate strategies to control folding and binding akin to biomolecules. The Iverson group has been developing a class of foldamers, called aedamers, which employ the aromatic-aromatic complexation between electronrich 1,8-dialkoxy-naphthalene (Dan) and electron-deficient 1,4,5,8-naphthalenevii tetracarboxylic diimide (Ndi) “building blocks”. It is expected that further work with these naphthyl oligomers will help establish aromatic interactions as a reliable tool for the construction of water-stable assemblies with tunable and predictable properties not found in nature. Overall, this dissertation describes the group’s first attempts to test the structural “designability” of naphthyl oligomers of previously unexplored sequences. Bottomline is that these studies have utilized the Dan:Ndi interaction to dictate intra- and inter- molecular associations to afford distinct folding topologies and achieve selective binding, respectively. Chapter 2 reports the observation that a previously studied amphiphilic aedamer happens to be an effective refolding inhibitor of RNase thus introducing the prospect of aedamer-protein interactions, a long-standing aim for these molecules. Chapter 3 presents the “shuffling” of the aedamer sequence (DanNdi)n to afford naphthyl oligomers, of the form Dann+1Ndin, that adopt turn structures. The results here demonstrate the ability of foldamers to access various secondary structures through changes to their primary sequence analogous to proteins. Chapter 4 details the first hetero-duplex system to operate via aromatic interactions in aqueous solutions. Dann and Ndin complementary strands exhibit high binding affinities and chain discrimination. The ability of the Dan:Ndi association to direct binding is expected to be extensively used by the laboratory to create discrete assemblies. As a whole, these projects probe the folding and binding of naphthyl oligomers in a variety of situations to demonstrate the wide reach of directed aromatic interactions to create various architectures. With this level of control established, surface patterning for microarrays, functional artificial proteins, biomolecule-aedamer ensembles, and other application-driven pursuits using naphthyl oligomers are possible in the near future.