With the support of this award from the Organic and Macromolecular Chemistry Program, Professor Jon Parquette of the Ohio State University will investigate peptide superstructures which are ubiquitous in the natural world and have shown tremendous potential for future biomedical applications. However, the availability of synthetic superstructures based on oligopeptides is still limited. This research will attempt to determine how the coupled conformational equilibria of peptides and dendrons within chimeric structures impact their propensity to assemble into higher-order structures. Attempts will be made to delineate the structural factors that determine the stability of higher-order peptide-dendron (PD) assemblies so that this knowledge can ultimately be used to reversibly control their structure and/or trigger their formation and destruction. Strategies to modulate the assembly of higher-order structures will not only be critical for the creation of "smart" electronic, optical, or bio-materials, but will also contribute to the knowledge-base that enables the development of therapies to reverse the beta-sheet self-assembly process leading to amyloid-based diseases such as Alzheimer's, Parkinson's, systemic amyloidosis, and type II diabetes. It is proposed to achieve this level of structural control by studying the properties of supramolecular assemblies composed of multiple structural elements, each of which exhibits unique and well-defined conformational equilibria.
Broader Impacts: Emerging technologies such as nano- and biotechnology, and materials chemistry are necessarily interdisciplinary in nature and many new career opportunities for chemists are materializing in these new technologies. The interdisciplinary nature of the work described in this proposal will teach students a variety of skills associated with the design and synthesis of supramolecular structures and will expose them to a broad range of computational and spectroscopic techniques. The development of methods to modulate the assembly of higher-order structures also has important biomedical and materials implications. A controllable self-assembly process will drive the creation of "smart" materials with extrinsically tunable physical, optical or electronic properties. Furthermore, the fundamental knowledge obtained in this work about the mechanism and dynamics of peptide aggregation will enable the development of molecular strategies to reverse the beta-sheet self-assembly processes leading to amyloid-based disease.
The spontaneous self-assembly of small molecules into highly ordered nanostructures produces many of the functional materials found in nature, ranging from the membranes of cell walls to the amyloid fibrils responsible for a variety of neurological disorders. Inspired by the efficiency, self-correcting capability and simplicity of molecular self-assembly, chemists have sought to replicate this process using designed building blocks programmed to organize into well-defined nanoscale objects. Although the level of complexity achieved by the de novo assembly of synthetic systems pales in comparison to that of natural systems, synthetic nanostructures have shown promise for applications in biomedical diagnostics, drug delivery, tissue engineering, optoelectronic and materials development. These applications require structural control at the nanoscale in order to achieve optimal performance. Although strategies to induce the spontaneous organization of small molecules have been developed, there is a need to find methods to create fully integrated functional systems. The research conducted under this grant award developed new strategies to control the hierarchical organization of multiple functional components at both the molecular and supramolecular levels. The specific focus of this work was broadly directed toward understanding how multiple elements of secondary structure in chimeric peptide-dendron structures were interdependent. Specifically, b-sheet-forming amphiphilic systems was developed as a particularly powerful strategy to direct the self-assembly of relatively simple peptide building blocks toward sophisticated nanostructures. Such peptide-based assemblers have shown significant potential in biomedical applications. Many of these applications would benefit from an ability to extrinsically modulate the structure and properties of the assembly. Although strategies for designing b-sheet forming peptides have been developed, the nature of the ultimate superstructure (tape, ribbon, fibril, or tube) is determined by the hierarchical packing of the b-sheet blocks. These studies have provided a new capability to precisely control the nature and properties of self-assembled nanostructures. Based on these initial results, we are applying these concepts to the creation of nanostructured optoelectronic materials constructed with multiple functional components.
