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

The active (D2HighR) and
inactive (D2LowR) 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 D2HighR active state. There is good agreement
between the calculated and experimentally measured D2HighR selectivity. In the ligand-binding site, the key amino acids identified
for D2HighR were Asp114(3.32) and Glu95(2.65), and for
D2LowR, it was Ser193(5.42). Moreover, analysis of replicate
MD trajectories demonstrated that the bromocriptine structure was
more rigid at the D2HighR state and more flexible at the
D2LowR state. However, the side chains of the ligand–receptor
complex of D2HighR showed larger variations relative to
the corresponding regions of D2LowR. 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.