Molecular modeling and molecular dynamics simulation-based structural analysis of GPR3

Abstract

G protein-coupled receptor 3 (GPR3) is an orphan GPCR; GPR3 has been reported to play a key role in Alzheimer’s disease through modulation of amyloid-beta production. The understanding of molecular mechanism involved has been limited due to unavailability of crystal structure of GPR3 and lack of different specific agonists. In this paper, we report the modeled 3D structure of GPR3 using threading and ab initio techniques with an objective to understand the mechanism underlying its interaction with agonists. The predicted model was optimized through 50 ns molecular dynamics simulation. Molecular dynamics (MD) simulation for 50 ns was performed on the 3D model of GPR3 embedded in 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine (POPC) lipid bilayer with aqueous system using OPLS (optimized potentials for liquid simulations) force field. The MD trajectories were analyzed to optimize the helical bundle conformations, active site, and 7TM domain variability during production phase of simulation. Binding pocket gave an insight into the size and chemical nature of compounds which could be potential agonists. The optimized structure would be significant in screening potential ligands through virtual screening.