Molecular modeling study on the dynamical structural features of human smoothened receptor and binding mechanism of antagonist LY2940680 by metadynamics simulation and free energy calculation
Molecular modeling study on the dynamical structural features of human smoothened receptor and binding mechanism of antagonist LY2940680 by metadynamics simulation and free energy calculation
复制标题
通过元动力学模拟和自由能计算对人平滑受体的动力学结构特征和拮抗剂LY2940680的结合机制进行分子建模研究。
DOI：
10.1016/j.bbagen.2014.03.010
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发表时间：
2014-07-01
影响因子：
3
通讯作者：
Yao, Xiaojun
中科院分区：
文献类型：
--
作者：
Bai, Qifeng;Shen, Yulin;Yao, Xiaojun
背景资料：Smoothened（SMO）受体是F-G类蛋白偶联受体（GPCRs）之一，是经典hedgehog信号通路的重要组成部分，在动物胚胎发育调控中起着关键作用。SMO受体的功能可以通过小分子激动剂和拮抗剂来调节，其中一些是潜在的抗肿瘤剂。方法：采用分子动力学模拟和动力学网络分析方法，研究SMO受体的动力学结构特征。结果：分子动力学模拟结果和动力学网络分析表明，螺旋VIII中保守的KTXXXW基序与螺旋I有较强的相互作用。跨膜6（TM6）的α-螺旋延伸被检测为配体结合口袋和拮抗剂解离途径的一部分。代谢动力学模拟结果说明了拮抗剂在SMO受体口袋中的结合机制，自由能计算表明拮抗剂需要克服约38 kcal/mol的能垒才能离开SMO受体的结合口袋。结论：异常长的TM6对拮抗剂在SMO受体口袋中的结合行为起重要作用。该结果不仅可以阐明该拮抗剂与F类GPCR之间的结合机制，而且可以为合理设计更有潜力的与SMO受体结合的小分子拮抗剂提供有用的信息。(C)2014爱思唯尔有限公司版权所有。
Background: The smoothened (SMO) receptor, one of the Class F G protein coupled receptors (GPCRs), is an essential component of the canonical hedgehog signaling pathway which plays a key role in the regulation of embryonic development in animals. The function of the SMO receptor can be modulated by small-molecule agonists and antagonists, some of which are potential antitumour agents. Understanding the binding mode of an antagonist in the SMO receptor is crucial for the rational design of new antitumour agents.Methods: Molecular dynamics (MD) simulation and dynamical network analysis are used to study the dynamical structural features of SMO receptor. Metadynamics simulation and free energy calculation are employed to explore the binding mechanism between the antagonist and SMO receptor.Results: The MD simulation results and dynamical network analysis show that the conserved KTXXXW motif in helix VIII has strong interaction with helix I. The alpha-helical extension of transmembrane 6 (TM6) is detected as part of the ligand-binding pocket and dissociation pathway of the antagonist. The metadynamics simulation results illustrate the binding mechanism of the antagonist in the pocket of SMO receptor, and free energy calculation shows the antagonist needs to overcome about 38 kcal/mol of energy barrier to leave the binding pocket of SMO receptor.Conclusions: The unusually long TM6 plays an important role on the binding behavior of the antagonist in the pocket of SMO receptor.General significance: The results can not only profile the binding mechanism between the antagonist and Class F GPCRs, but also supply the useful information for the rational design of a more potential small molecule antagonist bound to SMO receptor. (C) 2014 Elsevier B.V. All rights reserved.