H-Bonding Control of Molecular Self Assembly

Yale University, New Haven CT

Investigators

Abstract

With this award from the Organic and Macromolecular Chemistry Program, Prof. Andrew Hamilton will pursue the goal to develop strategies that exploit hydrogen bonding as a means of controlling molecular self-assembly. This represents an approach in which defined molecular shapes and interactions are built synthetically into individual components that then can self-assemble into a more complex aggregate. Most importantly the aggregate should possess properties and characteristics that are not present in the individual components. In the proposed project they will extend this approach to self-assembly particularly in aqueous solution with emphasis on targeting biological molecules. Their principal strategy will use the complementarity present in strands of DNA oligonucleotides as a way of bringing together organic fragments into aggregates that possess the property of biomolecule recognition. In this way they will be able to control the structure, stoichiometry and potential function of these aggregates through the chosen sequence and self-assembling properties of the oligonucleotides. Within this overall goal they will have three broad specific aims: 1- To use oligonucleotide aggregates on the cusp of stability to detect proteins. Complementary and fluorophore functionalized oligonucleotide strands that barely form a duplex under normal conditions will be stabilized by attaching physiologically important hydrophobic molecules (e.g. estrone, testosterone and other steroids). In the presence of the target protein (e.g. estrogen receptor) the stabilizing group will be sequestered, the duplex will dissociate and a fluorescent signal will be detected. 2- To develop bidentate protein binding agents self-assembled on duplex DNA. They will further investigate the use of DNA duplex as a scaffold for the formation of dynamic combinatorial libraries of protein binding agents. Attachment of two organic fragments onto the 3'- and 5'-ends of complementary DNA strands leads to the positioning of those fragments at one end of the duplex capable of targeting a protein surface. 3- To develop tetradentate protein binding agents self-assembled on quadruplex DNA. They will extend this approach to aggregates that present larger surface areas and that can target the exterior surface of proteins through the use of DNA quadruplexes. They will target these aggregates to tetrameric proteins such as neuraminidase and concanavolin-A. Broader Impacts - This work represents a new direction in chemistry, taking it not only into greater control of large molecular structures and their properties but also into aqueous environments and potential novel applications in biosensor design and protein binding agents. Students will gain broad experience in molecular design, synthesis, biochemistry and analysis of physicochemical properties. The PI has trained more than 110 student and post-doctoral coworkers and always has been deeply committed to the principles and practices of diversity. In recent years this has translated into a research group that has comprised, on average, around 50% of women and underrepresented minority students and post-docs. In his responsibilities as Provost of Yale, he has supported and initiated many programs for minority science students as well as broad initiatives focused on increasing the diversity of faculty, students and staff at Yale.