Abstract
The μ opioid receptor (μOR), which is part of the G protein-coupled receptors family, is a membrane protein that is modulated by its lipid environment. In the present work, we model μOR in three different membrane systems: POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), and DPPC (1, 2-dipalmitoyl-sn-glycero-3-phosphocholine) through 45 μs molecular dynamics (MD) simulations at the coarse-grained level. Our theoretical studies provide new insights to the lipid-induced modulation of the receptor. Particularly, to characterize how μOR interacts with each lipid, we analyze the tilt of the protein, the number of contacts occurring between the lipids and each amino acid of the receptor, and the μOR-lipid interface described as a network graph. We also analyze the variations in the number and the nature of the protein contacts that are induced by the lipid structure. We show that POPC interacts preferentially with helix 1 (H1) and helices H5-H6, POPE, with H5-H6 and H6-H7, and DPPC, with H4 and H6. We demonstrate how each of the three lipids shape the structure of the μOR.
Highlights
Opioid receptors, whose crystallographic structures were revealed in 2012 [1,2,3], are part of the largest group of integral membrane proteins, the G protein-coupled receptors (GPCRs) superfamily [4]
We compare the results obtained from a CG and an amino acid (AA) simulation of μ opioid receptor (μOR) embedded in a POPC membrane
As the CG model was directly obtained from the AA model, we compare the behavior of the same system with two different simulation methods
Summary
Opioid receptors, whose crystallographic structures were revealed in 2012 [1,2,3], are part of the largest group of integral membrane proteins, the G protein-coupled receptors (GPCRs) superfamily [4]. The structure of GPCRs consists of seven α-helices (H1-H7), followed by a short helix (H8), separated by three extracellular loops (EL1-EL3), and three intracellular loops (IL1-IL3). The N-terminal and C-terminal domains are located at the extra- and the intracellular side, respectively. Protein μ is the most important for the treatment of pain with morphine and opiate alkaloids. These drugs are addictive and their clinical efficacy is limited by side effects such as dependence and tolerance [5]
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