MOLECULAR DYNAMICS SIMULATION OF GPCR CB2 RECEPTOR IN LIPID BILAYERS AND QUANTU

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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. The marijuana (or cannabinoid, CB) receptors are classified as members of rhodopsin-like G-protein coupled receptors (GPCRs) family that represents ~45% of current drugs worldwide. In fact, due to the intrinsic properties of membrane proteins, very few high-resolution structures have been reported for any GPCRs due to the lack of high-quality crystals suitable for X-ray crystallography studies, or uniformly isotope-labeled "native" proteins for NMR studies. The most important is due to the fact that very limited protein expression systems have proven satisfactory for producing the full-length GPCRs in a functional state and with sufficient yields for biophysical studies. The objective of this research to further develop and improve our established CB2 membrane protein (MP) structural biology approaches, and then applies these structural and functional parameters to refine the homology-generated 3D CB2 structure model. The long range goal is to develop the CB2 receptor structure model for rational CB2 ligand design via understanding of the structural and functional events associated with CB2 receptor. Specifically, we will target the following aims: Aim1. MD simulations to refine the predicted 3D GPCR CB2 receptor structure models (preliminary work completed with two publications). Aim2: Further molecular dynamics (MD) calculations of the 3D CB2 receptor structure in membrane model (using GROMACS for MD simulation of the CB2 receptor in the lipid/water simulated bilayer membrane system. Such a large biosystem requires high power computing facility that is available @PSC. Aim3: Carry out receptor docking studies to explore the active ligand binding conformations and further evaluate the binding energy using QM approaches, including. GAUSSIAN for ab initio computations The accomplished work is expected to make a valuable contribution to cannabinoid research in particular and GPCR NMR structural biology in general. The potential significance of the work proposed is that it would contribute greatly to our ability to design immunomodulatory drugs that act solely at the cannabinoid CB2 receptor. These drugs could be potential therapeutic agents for autoimmune diseases and immunological disorders such as Multiple Sclerosis, Lupus, and neuroinflammatory pains, etc.