G protein-coupled receptors (GPCRs), one of the largest transmembrane protein families in the human genome, have seven transmembrane alpha helices and the third intracellular loop (ICL3) responsible for the G protein binding. Dopamine receptors are GPCRs, belonging to the class A family, which have been used as drug targets for the treatment of many neurological diseases such as Parkinson's disease, schizophrenia, etc. Recently, GPCR has been found to activate itself without any ligand bound under constitutive activity. While the sodium ions influenced the binding of ligands and the constitutive activity of receptors, the detailed modulation of sodium ions in GPCR signaling at atomic level is still unknown. Multi-micro seconds MD simulations were performed to study the allosteric sodium ion modulation in D3R signaling transmission under constitutive activity. The results showed that in the apo D3R system, the sodium ion enters from the extracellular site into the receptor to approach a highly conserved amino acid D2.50 and stabilizes there during the simulations. A hydrophobic layer below D2.50 hindered to form a continuous water channel. Moreover, the sodium ion did not enter the receptor D3R with dopamine bound in advance and formed a continuous water channel frequently due to the collapse of allosteric sodium ion pocket. Contrarily, the continuous water molecules in the D3R with sodium ion at D2.50 beforehand and dopamine bound were hindered by the hydrophobic layer, similar to the apo D3R system. G<sub>ai</sub> protein was then docked to the cytoplasmic region of D3R to perform the accelerated MD (flooding) simulations to study the sodium downstream existing from the receptor to form a continuous water channel. The study helps to explain the role of sodium ion in basal activity of D3R and to understand the signal transmission of D3R receptor.

<i>In silico</i> study of the allosteric effect of sodium ion on dopamine receptor D3R

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

In silico study of the allosteric effect of sodium ion on dopamine receptor D3R