Lipid bilayer molecular dynamics study of lipid-derived agonists of the putative cannabinoid receptor, GPR55
| Autor: | Patricia H. Reggio, Mary E. Abood, Diane L. Lynch, Evangelia Kotsikorou |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Polyunsaturated Alkamides
Stereochemistry medicine.medical_treatment Lipid Bilayers Population Molecular Conformation Phospholipid Arachidonic Acids Molecular Dynamics Simulation Ligands Biochemistry Article chemistry.chemical_compound Receptor Cannabinoid CB1 medicine Receptors Cannabinoid education Lipid bilayer Molecular Biology POPC Cannabinoid Receptor Agonists education.field_of_study Bilayer Organic Chemistry Hydrogen Bonding Cell Biology Ligand (biochemistry) chemistry Phosphatidylcholines Thermodynamics lipids (amino acids peptides and proteins) Cannabinoid Lysophospholipids Endocannabinoids |
| Zdroj: | Chemistry and Physics of Lipids. 164:131-143 |
| ISSN: | 0009-3084 |
| DOI: | 10.1016/j.chemphyslip.2010.12.003 |
| Popis: | Both L-α-lysophosphatidylinositol (LPI) and 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) have been reported to activate the putative cannabinoid receptor, GPR55. Recent microsecond time-scale molecular dynamics (MD) simulations and isothiocyanate covalent labeling studies have suggested that a transmembrane helix 6/7 (TMH6/7) lipid pathway for ligand entry may be necessary for interaction with cannabinoid receptors. Because LPI and 2-AGPI are lipid-derived ligands, conformations that each assumes in the lipid bilayer are therefore likely important for their interaction with GPR55. We report here the results of 70 ns NAMD molecular dynamics (MD) simulations of LPI and of 2-AGPI in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). These simulations are compared with a 70 ns simulation of the cannabinoid CB1 receptor endogenous ligand, N-arachidonoylethanolamine (anandamide, AEA) in a POPC bilayer. These simulations revealed that (1) LPI and 2-AGPI sit much higher in the bilayer than AEA, with inositol headgroups that can at times be solvated completely by water; (2) the behavior of the acyl chains of AEA and 2-AGPI are similar in their flexibilities in the bilayer, while the acyl chain of LPI has reduced flexibility; and (3) both 2-AGPI and LPI can adopt a tilted headgroup orientation by hydrogen bonding to the phospholipid phosphate/glycerol groups or via intramolecular hydrogen bonding. This tilted head group conformation (which represents over 40% of the conformer population of LPI (42.2 ± 3.3%) and 2-AGPI (43.7 ± 1.4%)) may provide a low enough profile in the lipid bilayer for LPI and 2-AGPI to enter GPR55 via the putative TMH6/7 entry port. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect