title: Novel computational methodologies for structural modeling of spacious ligand binding sites of G-protein-coupled receptors: development and application to human leukotriene B4 receptor.
abstract: This paper describes a novel method to predict the activated structures of G-protein-coupled receptors (GPCRs) with high accuracy, while aiming for the use of the predicted 3D structures in in silico virtual screening in the future. We propose a new method for modeling GPCR thermal fluctuations, where conformation changes of the proteins are modeled by combining fluctuations on multiple time scales. The core idea of the method is that a molecular dynamics simulation is used to calculate average 3D coordinates of all atoms of a GPCR protein against heat fluctuation on the picosecond or nanosecond time scale, and then evolutionary computation including receptor-ligand docking simulations functions to determine the rotation angle of each helix of a GPCR protein as a movement on a longer time scale. The method was validated using human leukotriene B4 receptor BLT1 as a sample GPCR. Our study demonstrated that the proposed method was able to derive the appropriate 3D structure of the active-state GPCR which docks with its agonists.
authors.affiliation: Graduate School of Innovation & Technology Management, Yamaguchi University, 2-16-1 Tokiwadai, Ube, Yamaguchi 755-8611, Japan. ishino.y@yamaguchi-u.ac.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishino
authors.forename: Takanori
authors.initials: T
authors.lastname: Harada
mesh_terms: D001665:Binding Sites / Q000502:physiology; D003205:Computing Methodologies; D006801:Humans; D007975:Leukotriene B4 / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C513240:LTB4R protein, human; D008024:Ligands; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4