Citation: LI Ai-Jing, XIE Wei, WANG Ming, XU Si-Chuan. Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D₃R[J]. Acta Physico-Chimica Sinica, ;2017, 33(5): 927-940. doi: 10.3866/PKU.WHXB201702211 shu

Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D₃R

Key Laboratory of Education Ministry for Medicinal Chemistry of Natural Resource, College of Chemical Science and Technology and Pharmacy, Yunnan University, Kunming 650091, P. R. China

Received Date: 19 October 2016
Revised Date: 21 February 2017

Fund Project: The project was supported from the National Natural Science Foundation of China (21163024, 21563032).

In this paper, based on the complex protein structure of third dopamine receptor (D₃R) with dopamine (DOP), we have studied the trajectories with the free energy changes of D₃R for DOP to move along its molecular channels and then probed the molecular dynamics mechanism of DOP transmitting along molecular channels, using molecular dynamics techniques including the potential mean force (PMF) of umbrella samplings from the GROMACS program (version 4.5). Simulation results show that for DOP located in the space region of D₃R to act as a neurotransmitter transmitting toward the outside of cell, the free energy change is 134.6 kJ·mol^-1 along the functional molecular channel of y+ axis within D₃R, and 211.5 kJ·mol^-1 along the y-axis towards the intracellular part. Within the structure of D₃R, the free energy changes are 65.8, 245.0, 551.4, 172.8 kJ·mol^-1 for DOP to transmit along the x+, x-, z+, z-axes, respectively, towards cell bilayer membrane, indicating that DOP leaves more easily along the x+ axis through the gap between TM5 (the fifth transmembrane helix) and TM6 (the sixth transmembrane helix) from the internal structure of D₃R. When free DOP molecules are located in the intercellular spaces, once they start moving along the inverse y+ axis direction under constant pressure and temperature, they spontaneously pass through the functional molecular channel to reach the space region of D₃R to act as a neurotransmitter, because the free energy change between DOP and D₃R along the inverse y+ axis direction is negative (－134.6 kJ·mol^-1). Therefore, DOP interacting with D₃R can easily play the role of a neurotransmitter. After DOP molecules have performed the actions of a neurotransmitter, they leave the internal structure of D₃R along the x+ axis of a protective molecular channel through the gap between TM5 and TM6 to avoid excessive function as transmitter. According to dopamine functional and protective molecular channels, we suggest new pathologies and the finding and development of new drugs for Parkinson's disease and schizophrenia.
- Dopamine,
- Dopamine receptor,
- Molecular channel,
- Molecular simulation,
- Parkinson's disease,
- Schizophrenia
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Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D₃R