LAUSR

In recent times, a significant portion of molecular simulation works have been focused on G-protein Coupled Receptors (GPCR). Given the fact that drug discovery paradigm has identified GPCR as important class as target membrane protein, molecular modelling of GPCR has itself become a unique area in the broad field of bio-molecular simulations. Atomistic simulation studies of GPCR provide rich information about ligand binding and the active conformation states related to onset of G-protein activation and downstream signaling. Starting with rhodopsin, the first GPCR to be reported for crystal structure, growing number of solved structures have opened up scopes for molecular simulation studies that potentially can assist novel design of high efficacy drugs molecules. In this presentation, we report our initial data on ongoing molecular docking and dynamics studies of the agonist-bound neurotension receptor. AMBER and GAFF force fields for organic molecules have been used to simulate the ligand/GPCR system under periodic boundary conditions. Three initial independent 50 ns molecular dynamics as well as docking studies show that natural agonist bound to the outer helical region has an unstable binding conformation in contrast to the agonist bound in the site embedded in intra-cellular helical region. Molecular docking using blind targeting of the X-ray protein structure also support our findings from initial molecular dynamics results. As neurotensin receptor is abundant both in brain and gastronomical regions, we are interested in active conformations of the receptor in physiological and acidic pH conditions. Delineation of energy and entropy in different constituent components in different pH medium by MM/PBSA and MM/GBSA techniques can provide information of neurotensin binding mode in different parts of human body.