The focus of this project is to understand the molecular basis of signal transduction via computer simulations of conformational changes in G protein-coupled receptors (GPCRs). These receptors are involved in many diverse physiological functions such as synaptic neurotransmission, sensory perception, attraction of motile cells by chemotaxis, and regulation of mitosis. These are also extremely common targets for pharmaceutical intervention. Despite the fundamental importance of GPCR signal transduction, a detailed understanding of the specific conformational changes involved and the physical-chemical forces behind them is lacking. This is primarily due to the experimental difficulties involved in expressing, purifying, and crystallizing these membrane proteins. In order to gain further understanding into the molecular mechanisms involving GPCR signaling, this project will focus first on rhodopsin, which is the best characterized GPCR and the only one with a detailed resting state structure determined by X-ray crystallography. This will be followed by calculations of the constitutive activity of opiod receptors, then the response to pH changes by the orphan receptors-OGR1 and GPR1. Computer simulations should provide significant insight into receptor activation. In particular, how small-scale, localized changes in structure due to the binding of a ligand, propagate to the larger-scale conformational changes that enable the receptor to interact with a G protein. It would be interesting to see whether this mechanism of activation is universal or at least common for this large and diverse family of receptors. The methodology to be developed in the course of this project is general and should be widely applicable to large-scale simulations of other biomolecular systems, and thus will have a broader impact. Moreover, graduate students will be involved in this project and are expected to carry out some aspects of the computer simulations.
