Effect of the membrane rigidity on the conformations of the µ opioid receptor

Opioid receptors (ORs), whose structures were revealed in 2012, are part of the G-protein coupled receptors (GPCRs), target of 50 % of drugs on the market today [1]. The structural and functional properties of transmembrane proteins are affected by the lipid environment [2-3].
To understand these properties, classical molecular dynamics (MD) simulations can provide numerous clarifications. Therein, we modelize a coarse-grained patch of a membrane with two phospholipids and µOR by NAMD (NAnoscale Molecular Dynamics) for 1 µs.

The two lipids considered to study the influence of the membrane rigidity on the µOR conformations are: DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholin) and an unsaturated one, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholin). More particularly, to study protein conformations, we examine the tilt of the seven transmembrane helices of µOR during the MD simulations for both types of membranes. As the DPPC is saturated, µOR is constrained in a rigid membrane and protein/lipid interactions are forced. The number of contacts between amino acids and lipids was calculated to highlight specific interaction sites for DPPC and POPC on the receptor. Our work demonstrates the crucial choice of lipids to perform MD by their impact on protein conformations [4].
Ultimately, our goal is to perform MD simulations with the most realistic lipid composition in order to guide docking experiments and explain the roles of lipids towards structural and functional properties of membrane proteins.

Bibliography:
[1] Manglik A., Kruse A., Kobilka T., Thian F., Mathiesen J., Sunahara R., Pardo L., Weis W., Kobilka B., Granier S., Crystal structure of the mu-opioid receptor bound to a morphinan antagonist, Nature, 2012, 485: 321-7.
[2] Jastrzebska B., Debinski A., Filipek S., Palczewski K., Role of membrane integrity on G protein-coupled receptors: rhodopsin stability and function, Progress in Lipid Research, 2011, 50: 267-77.
[3] Shang Y., Filizola M., Opioid receptors: structural and mechanistic insight into pharmacology and signaling, European Journal of Pharmacology, 2015, doi: 10.1016.
[4] Angladon M.A., Fossépré M., Leherte L., Vercauteren, D. P., How POPC, DPPC, and POPE interact with the µ opioid receptor: a coarse-grained molecular dynamics answer, in preparation.