G protein-coupled receptors (GPCRs), the largest membrane proteins, enable signal transduction through biological membranes and are responsible for a vast majority of physiological responses. Dopamine is a neurotransmitter in the central nervous system (CNS) which plays a pivotal role in the communication between neurons. Activation of dopamine receptors in the CNS regulates movement, cognition, and emotion. Dysfunction of these receptors may lead to severe nervous diseases. Although it is well known that agonist dopamine binds the receptor to activate and induce G protein binding for downstream signal transduction, the atomic level of G protein conformational change for further signaling remains unclear. Based on our previous study, multi-microseconds MD simulations were performed to investigate the conformational changes induced GDP/GTP exchange of Gai protein bound dopamine-D3R complex. The simulations showed that the helix a5 approaches the b6 and switch I flips out from switch II to cause GDP dissociation from Gai protein. The internal water molecules in dopamine-Gai-GDP-bound D3R complex were less due to the interference of hydrophobic layer in D3R, whereas the internal water molecules in dopamine-Gai-GTP-bound D3R complex were more enough to form a continuous water channel. Steered MD simulations also performed to calculate PMF of the two complexes for comparison. The PMF of dopamine-Gai-GDP-bound D3R complex was less than that of dopamine-Gai-GTP-bound D3R complex, meaning that GDP prefers dissociation from Gai protein. Moreover, the accelerated MD simulation (flooding) results showed that GDP fully dissociates from Gai protein, which is not apparently found in conventional MD simulations. The potential signal transmission pathway of activation mechanism from dopamine binding D3R through molecular switches to GDP/GTP exchange was finally proposed. Our results enable us to understand the receptor activation mechanism thoroughly and the downstream signaling pathway, which benefit in the drug development.

In silico study on the activation mechanism of dopamine receptor D3R bound G protein for downstream signal transmission

256th National Meeting (2018)

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