title: Computational Simulation of the Activation Cycle of Gα Subunit in the G Protein Cycle Using an Elastic Network Model.
abstract: Agonist-activated G protein-coupled receptors (GPCRs) interact with GDP-bound G protein heterotrimers (Gαβγ) promoting GDP/GTP exchange, which results in dissociation of Gα from the receptor and Gβγ. The GTPase activity of Gα hydrolyzes GTP to GDP, and the GDP-bound Gα interacts with Gβγ, forming a GDP-bound G protein heterotrimer. The G protein cycle is allosterically modulated by conformational changes of the Gα subunit. Although biochemical and biophysical methods have elucidated the structure and dynamics of Gα, the precise conformational mechanisms underlying the G protein cycle are not fully understood yet. Simulation methods could help to provide additional details to gain further insight into G protein signal transduction mechanisms. In this study, using the available X-ray crystal structures of Gα, we simulated the entire G protein cycle and described not only the steric features of the Gα structure, but also conformational changes at each step. Each reference structure in the G protein cycle was modeled as an elastic network model and subjected to normal mode analysis. Our simulation data suggests that activated receptors trigger conformational changes of the Gα subunit that are thermodynamically favorable for opening of the nucleotide-binding pocket and GDP release. Furthermore, the effects of GTP binding and hydrolysis on mobility changes of the C and N termini and switch regions are elucidated. In summary, our simulation results enabled us to provide detailed descriptions of the structural and dynamic features of the G protein cycle.
authors.affiliation: Korea Institute for Advanced Study, Seoul, Republic of Korea.
authors.forename: Min Hyeok
authors.initials: MH
authors.lastname: Kim
authors.affiliation: School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Hee Ryung
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Biological Engineering, Inha University, Incheon, Republic of Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Jeon
authors.affiliation: School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Jae Boong
authors.initials: JB
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Chung
authors.affiliation: School of Mechanical Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Moon Ki
authors.initials: MK
authors.lastname: Kim
mesh_terms: D000818:Animals; D002417:Cattle; D003198:Computer Simulation; D030562:Databases, Protein; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D013816:Thermodynamics; D019596:Wolves
chemical_list: D018343:Receptors, Adrenergic, beta-2; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs