Our research group is interested in understanding the intermolecular interactions of biological macromolecules: protein-protein, protein-nucleic acid, and protein-small molecule. Such interactions between proteins and ligands run nearly every aspect of biology, and we would like to understand them in quantitative, thermodynamic, and structural terms. To that end we study several examples using a range of experimental and theoretical biophysical tools. We apply ligand-binding theory, the quantitative treatment of interactions, to design experiments and analyse the results. Our experimental tools include calorimetry, surface plasmon resonance, NMR, x-ray crystallography, electronic spectroscopies, and others as each system requires. A recent addition to our toolkit is molecular dynamics simulations, which we apply to interpret experimental results and to design further experiments.
A fascinating non-linear property of protein interactions is cooperativity, also called allostery: the binding of one ligand alters the protein’s affinity for another, as in the interaction of oxygen with hemoglobin that becomes progressively stronger as the binding sites fill. In cooperative systems changes in ligand concentration elicit distinct physiological responses. How proteins mediate cooperativity has been studied for over 50 years without clear answers. It is widely thought to represent a new strategy in targeted drug design, but we can’t exploit it if we don’t understand it. Our recent work on the arginine regulatory system of E. coli highlights how very large-scale dynamics of the protein contribute to cooperativity, and shows how they are profoundly altered by the ligand. It is now generally believed that all dynamic proteins are allosteric. However, we also study the tryptophan regulatory system of E. coli, which offers an apparent exception that can test our understanding.