The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor-In Silico Study

The dopamine D-2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson's disease. The D-2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, which in both cases leads to the receptor coupling with a G protein. In addition to receptor modulation by orthosteric or allosteric ligands, it has been shown that lipids may affect the behaviour of membrane proteins. We constructed a model of a D-2 receptor with a long intracellular loop (ICL3) coupled with G(i alpha 1) or G(i alpha 2) proteins, embedded in a complex asymmetric membrane, and simulated it in complex with positive, negative or neutral allosteric ligands. In this study, we focused on the influence of ligand binding and G protein coupling on the membrane-receptor interactions. We show that there is a noticeable interplay between the cell membrane, G proteins, D-2 receptor and its modulators.