Molecular dynamics of a vasopressin V2 receptor in a phospholipid bilayer membrane

Molecular dynamics simulations were carried out for a V2 receptor (V2R) mod el embedded in a dimyristoylphosphatidylcholine (DMPC) bilayer. Both free a nd ligand-bound states of V2R were modeled. Our initial V2R model was obtai ned using a rule-based automated method for GPCR modeling and refined using constrained simulated annealing in vacuo. The docking site of the native v asopressin ligand was selected and justified upon consideration of ligand-r eceptor interactions and structure-activity data. The primary purpose of th is work was to investigate the usefulness of MD simulation of an integral m embrane protein like a GPCR receptor, upon inclusion of a carefully paramet erized surrounding lipid membrane and water. Physical properties of the sys tem were evaluated and compared with the fully hydrated pure DMPC bilayer m embrane. The solvation interactions, individual lipid-protein interaction a nd fluctuations of the protein, the lipid, and water were analyzed in detai l. As expected, the membrane-spanning helices of the protein fluctuate less than the peripheral loops do. The protein appears to disturb the local lip id structure. Simulations were carried out using AMBER 4.1 package upon con stant number-pressure-temperature (NPT) conditions on massively parallel co mputers Gray T3E and IBM SP2.