GPCR Handshake in the Spotlight: Exploring the Dimerization Interface of Dopamine D2 Receptors by Simulations at Multiple Resolutions

Abstract

Dopamine is an important central nervous system neurotransmitter, involved in the reward-response mechanism of the brain. Dopamine receptors belong to Class-A family of G Protein-Coupled Receptor (GPCR) superfamily and share the characteristic fold of seven transmembrane helices with the rest of the GPCR superfamily. It is known that a member of the dopamine receptor subfamily, Dopamine D2 receptor (D2R), forms dimers via transmembrane helix 4 (TM4). These TM4 dimers have been implicated in diverse pharmacological responses.The key to understanding the behavior of these dimers is the molecular basis of their dimerization. Although previous computational studies have investigated GPCR dimerization, a systematic sampling of conformational space has not been explored to find out the dimer interface in D2R. Our work focuses on this dimerization interface, involving TM4 helices of D2R. To begin with, a homology model derived from D3R crystallographic structure was used to develop a coarse-grained membrane model of TM4 dimers. A systematic biased Molecular Dynamics (MD) study was performed on this system to obtain the free-energy surface of dimerization. Our initial results suggest that D2R forms a TM4-TM4 dimer, with a free-energy profile characteristic of weak GPCR dimers. We are further analyzing the behavior of the D2R dimer, with TM4 interface, using all-atom MD simulations.To verify the possibility of other interfaces, we are investigating different dimer configurations by systematically varying the monomer orientation within them. These interfaces, such as the TM1/H8 interface, have been reported in dimers and higher-order oligomers of other GPCRs. A comparison between them and the TM4 interface will provide useful insights into D2R dimerization.