Exploring a model of a chemokine receptor/ligand complex in an explicit membrane environment by molecular dynamics...

The seven transmembrane helices G-protein-coupled receptors (GPCRs) form one of the largest superfamilies of signaling proteins found in humans. Homology modeling, molecular docking, and molecular dynamics (MD) simulation were carried out to construct a reliable model for CCR1 as one of the GPCRs and to explore the structural features and the binding mechanism of BX471 as one of the most potent CCR1 inhibitors. In this study, BX471 has been docked into the active site of the CCR1 protein. After docking, one 20 ns MD simulation was performed on the CCR1-ligand complex to explore effects of the presence of lipid membrane in the vicinity of the CCR1-ligand complex. At the end of the MD simulation, a change in the position and orientation of the ligand in the binding site was observed. This important observation indicated that the application of MD simulation after docking of ligands is useful. Explorative runs of molecular dynamics simulation on the receptor-ligand complex revealed that except for Phe85, Phe112, Tyr113, and Ile259, the rest of the residues in the active site determined by docking are changed. The results obtained are in good agreement with most of the experimental data reported by others. Our results show that molecular modeling and rational drug design for chemokine targets is a possible approach.