Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes

Focusing on the similarity and divergence of GPCR subtypes and their ligand interactions, we generated dopamine D-2, D-3, and D-4 receptor models based on the rhodopsin crystal structure and refined these with an extensive MM/MD protocol. After validation by diagnostic experimental data, subtype-specific relative positions of TM1, 2, 6, and 7 and bending angles of TM7 were found. To sample the conformational space of the complex, we performed simulated-annealing runs of the receptor protein with the sub-nanomolar antagonist spiperone. Docking a representative set of ligands, we were able to identify one superior model for each subtype when excellent correlations between predicted energies of binding and experimental affinities (r(2) = 0.72 for D-2, 0.91 for D-3 and 0.77 for D-4) could be observed. Further analysis revealed general ligand interactions with ASP3.32 and aromatic residues in TM6/7 and individual key interactions with TM1 and TM2 residues of the D-3 and D-4 receptor models, respectively.