DNA-Catalyst Conjugates for Site-Selective Transformations in Biological Contexts

The Chemistry of Life Processes Program in the Chemistry Division is funding Dr. David J. Gorin from Smith College to develop chemical reagents that selectively modify one compound in a complex biological mixture. Currently, transforming one molecular target in a mixture with many competing molecules is a major challenge for chemical researchers. The strategy being developed relies on DNA molecules capable of folding into complex three-dimensional structures and adhering to specific targets of interest. The DNA serves as an adhesive to bring a modifying chemical structure into close proximity, resulting in selective modification of the target. These new reagents are being applied to perturb and study molecular processes in living systems, including communication within bacterial populations that are important for understanding infections. Undergraduates at Smith College, the nation's largest liberal arts college for women, are key contributors to the research. In order to increase the Science, Technology, Engineering and Mathematics (STEM) undergraduate engagement and the success of women, and especially women of color, course-based research and guest lectures by diverse STEM role models are incorporated into the introductory organic chemistry classes. The impact of these and other curricular innovations are assessed through the deployment of a competition-based assessment plan for student capacities alongside more traditional approaches for tracking student outcomes.

The goal of this research is to develop reagents for the selective chemical modification of one target molecule in a complex biological mixture. A new class of selective catalysts that recognize and bind to a particular target, thereby increasing the rate of a desired reaction, are being developed. Specifically, selective and high-affinity DNA aptamers are being covalently linked to well-established low molecular weight catalysts, including organo- and transition metal-catalysts, to create DNA-small molecule catalyst conjugates (DCats). DCats enable enzyme-like selectivity with synthetic reagents, promising a fundamentally new capability to target a chemical reaction to any molecule of interest. Generality is being demonstrated in an array of reaction chemistries on both small molecules and protein substrates. In addition, a DCat is being developed to investigate N-acyl homoserine lactone chemical communication within populations of bacteria. This application demonstrates the broad potential of DCats as tools to study biological systems and other complex mixtures. Smith University undergraduates are centrally involved in the research, which represents a springboard for STEM graduate study and careers. Incorporation of the proposed research into the introductory organic chemistry laboratory class broadens the impact of the research by reaching a greater number of students, especially those who might not vigorously pursue research opportunities on their own initiative.