Comparison of Coarse-Grain and All-Atom Methods for the Study of 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].
To understand these processes, classical molecular dynamics (MD) simulations can provide numerous clarifications. We compare the results of CG (coarsegrained, 1 μs) and AA (all-atom, 17 ns) simulations for a patch of membrane with POPC (1-palmitoyl- 2-oleoyl-sn-glycero-3-phosphocholin) and the μ receptor by NAMD (NAnoscale Molecular Dynamic). CG simulations are quick but less accurate than AA simulations. We need them to demonstrate the role of lipids in μ conformations changes. For details and evidences, AA simulations are necessary.

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 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.
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