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. The long term goal of our NIH/NIDA (DA03934 and DA021358) funded research is to unravel at the molecular level, the mechanism of action of the cannabinoids. In part, this will entail understanding the activation mechanism of the CB1 receptor. This protein, a member of the rhodopsin-like Class A G-protein receptor family, is found primarily in the central nervous system, has several unusual features, including very lipophilic endogenous ligands, as well as, a high level of ligand-independent activation (constitutive activity). The work we propose here focuses on the role that the lipid itself plays in the stability and activation properties of CB1. In this proposal we request 497000 SUs on the Cray XT3 (BigBen) machine at the Pittsburg Supercomputing Center for the molecular dynamics simulation of the CB1 receptor in a fully hydrated phospholipid bilayer. We propose to run, using the scalable molecular dynamics engine NAMD2, several long (100ns) trajectories to ascertain the role that the lipid plays in the structure and dynamics of the CB1 receptor. Moreover, our request includes resources to build and evaluate the stability of the activated form of the receptor.