The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor

• DOI: 10.1038/srep22639
• Publication Date: 2016-03-04T10:34:45Z
• Authors: Nathaniel Stanley; Leonardo Pardo; Gianni De Fabritiis
• Keywords: Models, Molecular; 0301 basic medicine; Lipid Bilayers; Biological Transport; Molecular Dynamics Simulation; Ligands; Lipid Metabolism; Dinàmica molecular -- Simulació per ordinador; Neurotransmissors; Article; Receptors, Lysosphingolipid; 03 medical and health sciences

Abstract The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition at atomic level. In this work we succeeded in resolving lipid inhibitor ML056 sphingosine-1-phosphate receptor 1 (S1P R) using unbiased molecular dynamics simulations with aggregate sampling over 800 μs. pathway multi-stage consisting ligand diffusing leaflet contact “membrane vestibule” top TM 7, subsequently moving from lipid-facing vestibule orthosteric cavity channel formed by TMs and 7 N-terminal receptor. Unfolding alpha-helix increases volume upon entry, helping reach crystallographic pose that also corresponds predicted favorable pose. relaxation timescales show rate-limiting step multi microseconds timescale. We comment on significance parallels context other studies.