Effect of the phosphatidylcholine on the dynamical properties of the µ opioid receptor

Opioid receptors, whose structures were revealed in
2012, are part of the G-protein coupled receptor
(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]. For example, the hydrophobic
mismatch promotes dimerization by reducing the
entropy due to the adaptation of the membrane to
protein [3]. Dimerization of μ protein involves
different signaling pathways but are still poorly
understood.
To understand these processes, classical molecular dynamics (MD) simulations can provide numerous
clarifications. We modelize a coarse-grained patch of membrane with POPC (1-palmitoyl-2-oleoyl-snglycero-
3-phosphocholin) and the μ receptor by NAMD (NAnoscale Molecular Dynamic) for 1 μs.
Firstly, we examine the adaptation of the lipids to the receptor and vice versa. To explain such
adaptation, we examine precisely the interactions between the amino acids and lipids by calculating the
distance between each other and the tilt of the seven helices of the μ protein during the MD simulation.
Then, we study, via POCASA, the possible pockets on the protein to accomodate lipids and determine
differents key conformations through the clustering of the pockets. We further will use other lipids to
charaterize the different binding of the lipids on the μ receptor and show potential new conformations
of the μ receptor.
Ultimately, our goal is to perform MD simulations with the most realistic lipid composition, the
simplest and most significant in terms of protein/lipid interactions, in order to guide the docking
experiments and show the importance of the interaction of a protein with a lipid towards its structural
and functional properties.
Bibliography:
[1] Manglik A., Kruse A., Kobilka T., Thian F., Mathiesen J., Sunahara R., Pardo L., Weis W.,
Kobilka B., Granier S. (2012) Crystal structure of the mu-opioid receptor bound to a morphinan
antagonist Nature 485: 321-7
[2] Jastrzebska B., Debinski A., Filipek S., Palczewski K. (2011) Role of membrane integrity on G
protein-coupled receptors: rhodopsin stability and function Progress in Lipid Research 50: 267-77
[3] Soubias O., Niu S.-L., Mitchell D., Gawrisch K. (2008) Lipid-rhodopsin hydrophobic mismatch
alters rhodopsin helical content Journal of American Chemistry Society 130: 12465-71