Current Research Projects
A key feature of living systems is their ability to respond dynamically to stimuli, often through complex cascades of molecules mediated by non-covalent interactions. Detecting and quantifying these transient interactions is key to gaining a better understanding of how biological systems function. A number of innovative approaches to trapping and analyzing key intermediates have been developed, however, many of these techniques rely on the formation of covalent bonds which freeze the system under study in a particular moment, and don’t allow any subsequent responsiveness to successive stimuli. Accordingly, the development of molecular systems, which are capable of dynamic responsiveness, allows the potential to probe dynamic events without temporal isolation. I am currently interested in three primary projects using aqueous supramolecular chemistry to rationally develop systems capable of dynamic responsiveness to targeted stimuli.
Rylene Dyes as Dynamic Sensors for Host-Guest Encapsulation
The first project (Figure 1A) is based around the development of a modular platform for the detection of host-guest complex formation via displacement of a fluorescent sensor. Based on a tunable rylene imide scaffold (blue) conjugated to quaternary amines (red), a wide range of sensors with different binding specificities and emission wavelengths can be synthesized. When not encapsulated, the sensor has emission quenched by formation of an intramolecular charge transfer (CT) state through electron transfer (ET). The formation of this state is disfavored on encapsulation of the amine, leading to an increase in emission from the sensor. This proposal allows students to develop skills in organic synthesis, as well as a strong understanding of organic photochemistry through sensor development and testing. In addition to increasing our understanding of encapsulation events and how they effect charge separation in organic chromophores, the sensor has applications in facile screening of host-guest (G, purple) interactions for delivery systems as well as sequestration of contaminants.
Development of Quadruplex Nucleic Acids as micro-RNA Sensors
The second project is based around the development of a sensor platform for endogenous, disease-associated micro-RNA (miRNA) based on DNA structural transitions. The sensor makes use of the structural interconversion between a DNA quadruplex (Figure 1A, left) and a DNA duplex (Figure 1A, right) in response to recognition of an miRNA target, with a resulting fluorescence signal. The use of a DNA scaffold allows the sensor to be highly modular, capable of switching targets through simple exchange of the central recognition sequence. This proposal allows students to learn basic techniques relating to the synthesis, modification and manipulation of nucleic acids, as well as basic spectroscopic techniques. In addition to increasing our basic understanding of controlled structural transitions in nucleic acids (a topic of increasing interest and relevance to chemical biology) this project has the potential to specifically detect nucleic acid biomarkers in real time in living systems, with applications in early detection of cancer and tracking the spread of and mutation of viruses through viral RNA.
Aptamer-targeted Sensors Using Nucleic Acid Scaffolds
The third project (Figure 1C) is based around the use of nucleic acid aptamers (specific sequences capable of strong, specific binding to small molecule targets) to create a platform for the real-time detection of small molecules via fluorescence signals. Nucleic acid strand exchange mechanisms will be utilized to create sensors that will be capable of responding to shifts in analyte concentration in real time. These systems can also be made recyclable through subsequent deactivation and reactivation steps utilizing duplex strand invasion. This proposal allows students to become familiar with the manipulation and study of nucleic acids, as well as basic spectroscopic techniques. In addition to increasing our basic understanding of nucleic acid-small molecule interactions, this project potential to allow the development of highly specific and quantitative sensors able to detect environmental contaminants.