B.Sc. (University of Guelph Biophysics 1996)
Ph.D. (University of Toronto Biochemistry 2003)
- Chemical Biology
- Chemical Physics
The focus of our lab is biomolecular dynamics. We seek to understand how proteins, DNA, RNA, and metabolites change shape, react, and assemble with one another. This knowledge aids the development of new types of drugs and bioinspired materials and sheds light on the physical chemical principles that underlie living systems.
Our approach is based on three complementary pillars: experiments – we design new methods to measure WHAT biomolecules are doing, as they do it; theory – we use Physical Chemistry to better explain WHY they behave the way they do; and computation – we write computer code that integrates experimental data and theoretical models to give detailed descriptions of biomolecular function that are thermodynamically and kinetically correct. Individual projects lean more heavily toward one pillar or another, or to practical applications. Nevertheless, the three-pronged experimental-theoretical-computational approach informs all the work we do and gives us a unique toolkit for observing biomolecules in action.
We use a variety of instrumentation to measure biomolecular dynamics. These include: Isothermal Titration Calorimetry (ITC) measures the heat released or absorbed by chemical and biological processes in real time. It is typically used simply to measure binding affinity, but our lab is spearheading new ITC methods for measuring complex enzyme kinetics. Thermal hysteresis (TH) pushes biomolecular systems out of equilibrium by rapidly raising and/or lowering the temperature while making spectroscopic measurements. We develop new ways to unravel intricate folding and assembly processes using TH experiments. Nuclear Magnetic Resonance (NMR) spectroscopy detects signals from individual nuclei in biomolecules and gives atomic-resolution information on structure and dynamics. Differential Scanning Calorimetry (DSC) measures the heat absorbed as structured biomolecules melt at high temperature.
Current projects include:
- DNA and RNA can adopt an enormous diversity of folded structures. It is thought that this plays a key role in controlling gene transcription and translation, but how this works in practice is not well understood. We are trying to define the relationships between nucleotide sequence, structure, and flexibility.
- We are developing new drug discovery approaches, for instance designing drugs that activate pathogenic kinases to perform background ATP hydrolysis or designing inhibitors of metabolic enzymes that cannot be out-competed by the resulting accumulation of substrates. (with the Moitessier lab)
- We are using a combination of biophysical and protein engineering approaches to develop nanostructured materials based on filamentous viruses (with the Blum lab).
- We are using NMR spectroscopy to unravel how lanthipeptide natural products are synthesized by specialized modifying enzymes (with the Thibodeaux lab)
- We are devising TH methods to better understand small-molecular directed nucleic acid assembly (with the Sleiman lab)
- We are designing drugs to inhibit RNA riboswitches, a promising new class of antiobiotic targets. (with the Moitessier and McKeague labs)