The G Protein-Coupled Receptor (GPCR) super family contains over 800 receptors sharing a similar method of signal transduction but varying greatly in ligand recognition and function. The past few years have provided a wealth of structural information with 13, and counting, unique receptor crystal structures solved to date. As more than a third of the drugs currently on the market act at GPCRs, they are profoundly important drug targets. Despite this, the structural aspects that contribute to their selectivity are poorly understood.

Molecular Dynamics simulations of GPCRs embedded in a solvated bilayer can provide detailed insight into the binding pathway and intermediate binding sites of antagonists by initially placing them outside of the receptor. By comparing the binding pathways between the D₂ and D₃ dopamine receptors we can gain a better understanding of the structural features of antagonist and receptor that contribute to their selectivity. The information revealed would be particularly relevant to antipsychotics, a class of drugs restricted in their use primarily due to their poor selectivity and consequent side effects.

In this work we have performed molecular dynamics simulations of the D₂ and D₃ dopamine receptors containing a variety of antagonists using a solvated bilayer system. The bilayer was constructed around D₂R and D₃R models adapted from the D₃R crystal structure. United atom POPC lipids were positioned around the protein and the system was then solvated with TIP3P water molecules in order to keep the system as computationally efficient as possible without sacrificing the accuracy of the simulations.