Allosteric modulation of protein function
Nature is replete with examples of processes (photosynthesis, respiration, apoptosis, cell signalling to name a few) which require biomolecules to carry out biochemical and biophysical operations in response to optical and physicochemical triggers. In this research we aim to understand how biomolecules propagate signals over distance (allosterically) from optical and physicochemical trigger events to produce two specific functional responses: 1) catalysis, and 2) ligand release. In one study we are looking at G-protein coupled receptors (GPCR), which are helical proteins located on the cell surface and which react to impulses (light, interaction with small molecules, etc) from the outside of the cell to trigger ligand release from a partner protein (G-protein) inside the cell. While the allosteric response of GPCR is well documented, the mechanism of allostery is unknown. We are elucidating the underpinnings of allostery in this system through theoretical/computational modeling and simulations (left and right panels in the figure above). In a second study, we are examining the spatiotemporal extent of protein motions which control the hydroxylation reaction catalyzed by the P450 class of enzymes. The motivation is to identify long range collective motions which can project onto the different steps of the catalytic cycle to provide an allosteric means to control the chemical reaction. The overall goal of our research is to develop a computational framework to identify allosteric binding sites for inhibitors/activators (red/green spheres in centre panel of the the figure) which can modulate the biophysical and biochemical properties of proteins.