LONG TIME-SCALE DYNAMICS OF G-PROTEIN COUPLED RECEPTORS IN EXPLICIT LIPID ENVIR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. G-protein coupled receptors (GPCRs) constitute the largest family of membrane proteins used by cells to communicate with their environment. Lack of good expression levels and crystallization issues have obstructed obtaining experimental structures for these proteins, that constitute about 50% of the current pharmaceutical targets. Our group has developed methods [1] to obtain structures of these GPCRs in apo and ligand-bound forms. To gain a detailed molecular perspective on the function of these proteins, it is critical to sample and understand their structures in activated and deactivated forms in their native cell environment, both in the absence and presence of ligands. Conformational changes, which are associated with activation, are known to occur in these receptors on micro to millisecond time scales and are still beyond the reach of current all-atom molecular dynamics simulations. This application for a development grant will focus on performing these simulations using NAMD [2] to experiment with the time scales necessary and sufficient to validate structural models of these proteins and to test the stability of apo and ligand-bound proteins in explicit lipid environment. The conformational changes in these proteins will also be studied using steered dynamics to explore interconversions between their activated and inactivated forms. The information obtained from this development grant will assist us in developing a full MRAC/LRAC proposal to focus on a few pharmaceutical target GPCRs, for which we have obtained structures in apo and ligand-bound forms, and for which an understanding of dynamics and function will provide potential drug candidate leads that can act as selective and effective agonists or antagonists. [1] Vaidehi et al. Proc. Natl. Acad. Sci. USA 99, 12622 (2002) [2] Phillips et al. J. Comp. Chem. 26, 1781 (2005).