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. 2016 Dec 13;12(12):e1005240.
doi: 10.1371/journal.pcbi.1005240. eCollection 2016 Dec.

Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of μ-Opioid Receptors in a Multi-component Plasma Membrane Model

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Impact of Lipid Composition and Receptor Conformation on the Spatio-temporal Organization of μ-Opioid Receptors in a Multi-component Plasma Membrane Model

Kristen A Marino et al. PLoS Comput Biol. .
Free PMC article

Abstract

The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with the receptor, and/or indirectly, by altering the bulk properties of the membrane. While the exact role of oligomerization in the function of class A GPCRs such as the μ-opioid receptor (MOR) is still unclear, insight as to how these receptors oligomerize and the relevance of the lipid environment to this phenomenon is crucial to our understanding of receptor function. To examine the effect of lipids and different MOR conformations on receptor oligomerization we carried out extensive coarse-grained molecular dynamics simulations of crystal structures of inactive and/or activated MOR embedded in an idealized mammalian plasma membrane composed of 63 lipid types asymmetrically distributed across the two leaflets. The results of these simulations point, for the first time, to specific direct and indirect effects of the lipids, as well as the receptor conformation, on the spatio-temporal organization of MOR in the plasma membrane. While sphingomyelin-rich, high-order lipid regions near certain transmembrane (TM) helices of MOR induce an effective long-range attractive force on individual protomers, both long-range lipid order and interface formation are found to be conformation dependent, with a larger number of different interfaces formed by inactive MOR compared to active MOR.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
The normalized probability distribution of the A) PC, B) PE and C) SM lipids around the inactive and active receptor protomers (top and bottom panels, respectively) during the simulations with low receptor density and position restraints on the receptors. The center of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. The helices of the crystal structures used as the starting structures are colored according to the same color scheme.
Fig 2
Fig 2
The normalized probability distribution of CHOL around A) inactive and B) active MOR protomers during the simulations with low receptor density and position restraints on the receptors. The center of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. Also shown are structures of the inactive and active MOR with the residues colored by their probability of being in contact with the ROH bead of a CHOL (white to blue to green indicates low to high probability).
Fig 3
Fig 3. Plots showing the average lipid order (left column) and bilayer thickness (nm, right column) during the final 2 μs of a simulation run of inactive (top row) or active (bottom row) receptors in the low receptor density membrane with position restraints on the receptors.
The data is averaged over all lipids, excluding the ones that flip-flop across the membrane (i.e. CHOL, CER, and DAG). For the order, a value of 0 (orange color) indicates a fully ordered lipid tail, and the larger the value, the more disordered the tail. The units of thickness are nm. In both cases, the white color is set to the average value of the simulations with the inactive receptors. The center of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively.
Fig 4
Fig 4. The bilayer thickness (nm, top row) and lipid order (bottom row) of the non-flipping lipids within 3.125 nm of the protein center of mass as a function of the helix index for the low receptor density simulations in which the proteins were permitted to move freely.
For the thickness, the average and standard error are indicated by a black line and a grey band, respectively. The overall average value of the order is indicated by a red dashed lines in the bottom panels. The location of the center of mass of the helices is indicated by the vertical lines and TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink, respectively. Because of the large tilt of TM3, its center of mass appears to the right of TM4.
Fig 5
Fig 5
Average lipid thickness (upper triangle) and order (lower triangle) as a function of protein-protein distance r and lipid position d for interfaces TM5/TM5 and TM1,2,H8/TM1,2,H8 between inactive receptors (panels A and B, respectively).
Fig 6
Fig 6. The average order of CHOL molecules in the lipid headgroup region of the upper and lower leaflets next to the inactive receptors (top) and activated receptors (bottom) during the final 2 μs of the low receptor density simulations with the backbone beads kept fixed.
In both cases, the white color is set to the average value of the simulations with the inactive receptors. The center of mass of the seven TM helices are indicated by the colored dots as follows: TMs 1 through 7 are colored in blue, red, grey, orange, yellow, green, and pink.
Fig 7
Fig 7. Distribution of CHOL in the plasma membrane with inactive receptors, activated receptors, or no proteins as a function of the z-coordinate and lipid order.
The simulations with the receptors are those with high receptor density and the receptor backbone beads kept fixed. The middle of the membrane is set to z = 0.
Fig 8
Fig 8
Schematic of the interfaces formed by a) two inactive receptors, b) two active receptors, and c) one active and one inactive receptor. The opacity of the color linking the two sides indicates the probability of formation

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