Contribution
of the binding site residues and lipids to the overall
binding of ORG27569 to CB1R (PDB ID 6KQI). (A) Contact frequency (%) of ORG27569
accounts for the extent of molecular interactions with the binding
site residues. The contact frequency represents the fraction of the
total simulation time during which a given residue is within 4 Å
of the ligand. For example, the binding site residues, C2384.47, W2414.50, and F2374.46, are in close contact
with ORG27569 for >95% of the simulation time. (B) Several membrane
lipids such as cholesterol, POPC, POPE, POPI, and POPS are directly
in contact with ORG27569 likely stabilizing the ligand within the
binding site, as observed during the 1 μs long unbiased all-atom
MD simulation. (C) Distances between ORG27569 and several lipids were
monitored during the entire simulation. The dotted lines represent
an arbitrary 4 Å distance in the graphs. The distances are shown
for cholesterol (CHOL1, deep sky blue), phosphatidylcholine (POPC2,
black), phosphatidylethanolamine (POPE4, blue), phosphatidylinositol
(POPI5, purple), and phosphatidylserine (POPS6, red).