Structural Investigation of the Dopamine-2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR...

The active (D2^HighR) and inactive (D2^LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2^HighR active state. There is good agreement between the calculated and experimentally measured D2^HighR selectivity. In the ligand-binding site, the key amino acids identified for D2^HighR were Asp114(3.32) and Glu95(2.65), and for D2^LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2^HighR state and more flexible at the D2^LowR state. However, the side chains of the ligand-receptor complex of D2^HighR showed larger variations relative to the corresponding regions of D2^LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding.