title: GDP release preferentially occurs on the phosphate side in heterotrimeric G-proteins.
abstract: After extra-cellular stimulation of G-Protein Coupled Receptors (GPCRs), GDP/GTP exchange appears as the key, rate limiting step of the intracellular activation cycle of heterotrimeric G-proteins. Despite the availability of a large number of X-ray structures, the mechanism of GDP release out of heterotrimeric G-proteins still remains unknown at the molecular level. Starting from the available X-ray structure, extensive unconstrained/constrained molecular dynamics simulations were performed on the complete membrane-anchored Gi heterotrimer complexed to GDP, for a total simulation time overcoming 500 ns. By combining Targeted Molecular Dynamics (TMD) and free energy profiles reconstruction by umbrella sampling, our data suggest that the release of GDP was much more favored on its phosphate side. Interestingly, upon the forced extraction of GDP on this side, the whole protein encountered large, collective motions in perfect agreement with those we described previously including a domain to domain motion between the two ras-like and helical sub-domains of G(α).
authors: Institut des Biomolécules Max Mousseron-IBMM, CNRS UMR5247, Université Montpellier 1, Université Montpellier 2, Faculté de Pharmacie, Montpellier, France.
authors: Maxime
authors: M
authors: Louet
authors: Jean
authors: J
authors: Martinez
authors: Nicolas
authors: N
authors: Floquet
mesh_terms: D019295:Computational Biology / Q000379:methods*; D006153:Guanosine Diphosphate / Q000737:chemistry* / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D006153:Guanosine Diphosphate; D020962:Heterotrimeric GTP-Binding Proteins