title: The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor.
abstract: The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition process at the atomic level. In this work we succeeded in resolving the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a "membrane vestibule" at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the "membrane vestibule" is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies.
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Stanley
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain.
authors.forename: Gianni De
authors.initials: GD
authors.lastname: Fabritiis
mesh_terms: D001692:Biological Transport; D008024:Ligands; D008051:Lipid Bilayers / Q000378:metabolism*; D050356:Lipid Metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D049349:Receptors, Lysosphingolipid / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D008051:Lipid Bilayers; D049349:Receptors, Lysosphingolipid