Insights into the conformational perturbations of novel agonists with 尾3-adrenergic receptor using molecular dynamics simulations

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• 作者：Parul Tewatia^a ; Nikhil Agrawal^b ; Mahendra Gaur^b ; Shakti Sahi^b ; ^{shaktis@gbu.ac.in" class="auth_mail} ; ^{shaktisahi@gmail.com" class="auth_mail}
• 关键词：Molecular dynamics simulation ; Beta 3-adrenergic receptor ; Molecular docking
• 刊名：Biochimie
• 出版年：June, 2014
• 年：2014
• 卷：101
• 期：Complete
• 页码：168-182
• 全文大小：4105 K

文摘

Beta 3-adrenergic receptors (尾3-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 尾3-AR is not known. Molecular dynamic simulations (100聽ns) were performed on the 3-D molecular model of 尾3-AR and complexes of 尾3-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 尾3-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 尾3-AR. The compound 3, 4 and 6 are proposed to act as scaffolds for potential agonists for 尾3-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 尾3-AR.