Construction of a synaptic membrane for in silico endocannabinoid investigations

The mechanism of a chemical reaction cannot be assumed prior to identifying the solvent, thus to accurately model membrane-bound cannabinoid receptors, details of the lipid bilayer must be considered as well. Traditionally thought of as a permeable barrier, the membrane also serves as a medium for hydrophobic ligand delivery; the Reggio group has published on the entry of sn-2-arachidonoylglycerol into the cannabinoid CB2 receptor through the trans-membrane region. Currently receptor and ligand trajectories are calculated in a single-phospholipid bilayer, however biological membranes are comprised of many lipid species. Herein nanosecond timescale molecular dynamics studies of various membrane compositions are reported, culminating to a final model mimicking a synaptic plasma membrane in phospholipid composition. Structural changes to phospholipids in increasingly heterogeneous compositions are discussed, along with interactions between endocannabinoid N-arachidonoylglycine (NAGly) and membrane components. The final model provides a significant contrast to a pure phosphatidylcholine bilayer, in addition to proposing new investigations of ligand diffusion, phospholipid clustering, and similar hydrogen bonding studies