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

• Published in: Biochimica et biophysica acta Vol. 1840; no. 7; pp. 2128 - 2138
• Main Authors: Bai, Qifeng, Shen, Yulin, Jin, Nengzhi, Liu, Huanxiang, Yao, Xiaojun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2014
• Subjects: agonists; Amino Acid Sequence; antagonists; antineoplastic activity; antineoplastic agents; dissociation; embryogenesis; energy; Free energy calculation; G-protein coupled receptors; Gibbs free energy; GPCR; Humans; Metadynamics; Models, Molecular; Molecular Dynamics Simulation; molecular models; Phthalazines - chemistry; Phthalazines - pharmacology; Protein Binding; Protein Structure, Secondary; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Smoothened Receptor; GPCR; Smoothened receptor; Molecular dynamics simulation; Free energy calculation; Metadynamics
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.03.010

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. 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. The MD simulation results and dynamical network analysis show that the conserved KTXXXW motif in helix VIII has strong interaction with helix I. The α-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 38kcal/mol of energy barrier to leave the binding pocket of SMO receptor. The unusually long TM6 plays an important role on the binding behavior of the antagonist in the pocket of SMO receptor. 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. •We build a model of SMO receptor in complex with explicit water, ions and lipids.•We explore the conserved structure of SMO receptor using dynamical network analysis.•The dissociation mechanism of an antagonist in the pocket of SMO receptor was analyzed.•TM6 plays an important role in the binding and unbinding process of an antagonist.