FIGURE 1.

Differences in how opioid ligands partition into the lipid bilayer. (A) Fentanyl molecules (orange) rapidly partitioned into the lipid membrane (grey). (B) Morphine molecules (orange) did not fully enter the lipid membrane (grey) but interacted with the charged lipid headgroups. Note while ligands can appear on either side of the bilayer due to the periodic boundary conditions applied in these simulations, for clarity only ligands in the upper leaflet of the membrane are shown. In no simulation did a ligand travel all the way through the bilayer. The protein is coloured according to residue properties (hydrophobic; grey, polar; green, acidic; red, basic; blue). (C) Distance between the center of mass of the ligand and the phosphate head groups (PO4 beads) of the lipid bilayer. Both the charged and neutral forms of fentanyl partitioned significantly deeper in the membrane than morphine. *p < 0.05, one-way ANOVA. Each data point represents the average distance between a fentanyl molecule and the PO4 beads over the entire simulation. (D) Free energy change for ligands moving between the bilayer center and the aqueous solvent. Calculated from PMF profiles shown in Supplementary Figure S3. Data plotted as mean ± error calculated from bootstrap analysis.