Insights into the conformational perturbations of novel agonists with β3-adrenergic receptor using molecular dynamics simulations

Beta 3-adrenergic receptors (β3-AR), belonging to the G-protein coupled receptor family, are known to be involved in important physiological functions as intestinal smooth muscle relaxation, glucose homeostasis etc. Detailed insight into the mechanistic mode of β3-AR is not known. Molecular dynamic simulations (100 ns) were performed on the 3-D molecular model of β3-AR and complexes of β3-AR with potential agonists embedded in 2-dipalmitoyl-sn-phosphocholine (DPPC) bilayer-water system using OPLS (Optimized Potentials for Liquid Simulations) force field to gain structural insight into β3-AR. The detailed structural analysis of the molecular dynamic trajectories reveal that the helical bundle conformations remain well preserved to maintain a conformation similar to the other X-ray solved G-protein coupled receptors, whereas significant flexibility is observed in intracellular and the extracellular loops region. The formation of extensive intra helical and water mediated H-bonds, and aromatic stacking interactions play a key role in stabilizing the transmembrane helical bundles. These interactions might be specific to the functional motifs such as D(E)RY, CWxP, S(N)LAxAD, SxxxS and NPxxY motifs which provide structural constraints on the β3-AR. The compound 3, 4 and 6 are proposed to act as scaffolds for potential agonists for β3-AR based on stereochemical and energetic considerations. In lieu of the lack of the crystal structure available, the findings of the simulation study provides more comprehensive picture of the functional properties of the β3-AR.