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Acta Physico-Chimica Sinca  2017, Vol. 33 Issue (5): 927-940    DOI: 10.3866/PKU.WHXB201702211
ARTICLE     
Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D3R
Ai-Jing LI,Wei XIE,Ming WANG,Si-Chuan XU*()
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Abstract  

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.



Key wordsDopamine      Dopamine receptor      Molecular channel      Molecular simulation      Parkinson's disease      Schizophrenia     
Received: 19 October 2016      Published: 21 February 2017
MSC2000:  O641  
Fund:  the National Natural Science Foundation of China(21163024);the National Natural Science Foundation of China(21563032)
Corresponding Authors: Si-Chuan XU     E-mail: sichuan@ynu.edu.cn
Cite this article:

Ai-Jing LI,Wei XIE,Ming WANG,Si-Chuan XU. Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D3R. Acta Physico-Chimica Sinca, 2017, 33(5): 927-940.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201702211     OR     http://www.whxb.pku.edu.cn/Y2017/V33/I5/927

DOPETQDOPETQDOPETQDOPETQ
Ile43 Asp110Asp110 Tyr191His349His349
Leu71 Met113Val111Ser192Ser192Val350Val350
Ala74 Met112Ser193Ser193Thr353Thr353
Asp75 Cys114Cys114 Val194 Tyr365
Leu76 Thr115Thr115 Ser196 Thr368
Val78 Ser117Leu168Phe197Phe197 Thr369
Ala79 Ile118Cys181Phe201Tyr198 Trp370
Val82Val82Leu121Ser182Phe338 Gly372Gly372
Met83Val86 Ile183Trp342Trp342Tyr373Tyr373
Leu89 Phe188Leu343 Asn375
Phe106Val189Val189Phe345Phe345Ser376
Val107 Ile190Phe346Phe346
Table 1 The residues within 0.6 nm of the D3R structure around ETQ and DOP
Fig 1 (a) Original graph of mutated protein crystal structure of dopamine third receptor with ETQ13; (b) molecular structures of ETQ and DOP; (c) human′s dopamine third receptor complex structure with dopamine14
Fig 2 Research materials: the complex structure of D3R with DOP including the double layer phospholipid POPC-H2O membrane
Fig 3 (A) Six orientations for DOP to move within D3R, and the tracks to move toward the outside of cell supposed along the y+ axis and toward the inside of cell along the y-axis, along the x+, x-, z+, z-axes for DOP from the interior of D3R to move into the POPC phospholipid bilayer membrane; (o, a, b, c) four pictures of the tracks along the y+ axis for DOP to move; (B) the potential of mean force (PMF) of the track along the y+ axis for DOP to move
n D/nm n D/nm n D/nm n D/nm n D/nm
0 (o)01000.641491.211991.852432.46
100.041030.711521.262001.902462.53
150.101050.771541.312071.932542.61
270.141110.791631.382081.96263 (c)2.65
440.201120.84169 (b)1.412112.012712.72
490.251130.881721.492152.063252.78
760.291170.921731.542212.083342.82
850.341380.981741.582232.154082.83
900.401411.031771.632252.20
920.441431.091791.712282.24
930.511451.131801.742332.28
94 (a)0.581461.181851.812372.42
Table 2 Umbrella samplings obtained by dopamine moving within D3R along the y+ axis
Fig 4 (o, a, b, c) Four pictures of the tracks along the y-axis for DOP to move; (A) potential of mean force (PMF) of the track along the y-axis for DOP to move within D3R
n D/nm n D/nm n D/nm n D/nm n D/nm
1 (o)0610.541191.111651.702062.23
20.05660.571261.141661.712112.28
80.09670.631271.191671.802172.33
180.14680.68132 (b)1.241701.852272.39
240.18800.721351.291711.902332.44
30 (a)0.24840.781381.331751.93239 (c)2.49
370.31870.831411.441761.982472.53
390.34950.911461.501792.052632.59
410.38970.951511.551802.102812.64
490.431041.011571.601852.144132.66
510.471111.051641.651992.19
Table 3 Umbrella samplings obtained by dopamine moving within D3R along the y-axis
Fig 5 (o, a, b, c) Four pictures of the tracks along the x+ axis for DOP to move from within D3R into the POPC phospholipid bilayer membrane on the main view and top view respectively; (A) PMF of the track along the x+ axis for DOP to move
n D/nm n D/nm n D/nm n D/nm n D/nm
4 (o)072 (a)0.41980.651221.061331.41
80.05730.42990.781241.091491.46
220.08740.471020.831251.141651.47
350.12880.531030.88129 (c)1.164631.48
470.17940.561070.911301.264641.47
670.22960.611080.971311.294781.49
710.2997 (b)0.691131.021321.384831.49
Table 4 Umbrella samplings obtained by dopamine moving within D3R along the x+ axis
n D/nm n D/nm n D/nm n D/nm n D/nm
1 (o)0610.471150.981791.382301.83
50.04640.531171.041921.432541.86
110.09650.591321.071961.472601.90
180.13660.641381.132011.53264 (c)1.93
370.19730.681421.182041.582651.96
410.2080 (a)0.731501.222171.623911.96
420.26870.771721.242231.673971.97
470.33910.831741.282261.723991.98
480.38920.871751.312271.744091.99
570.421070.93177 (b)1.352281.784142.02
Table 5 Umbrella samplings obtained by dopamine moving within D3R along the x-axis
Fig 6 (o, a, b, c) Four pictures of the tracks along the x-axis for DOP to move from within D3R into the POPC phospholipid bilayer membrane on the main view and top view respectively; (A) PMF of the track along the x-axis for DOP to move
n D/nm n D/nm n D/nm n D/nm n D/nm
5 (o)01150.521920.962261.332571.94
120.051260.581940.982281.382582.16
380.11130 (a)0.621991.022301.412622.20
520.151540.672041.08235 (b)1.472692.23
620.201590.722081.132381.53288 (c)2.26
690.241640.772151.182471.563742.29
760.301660.822201.192491.623922.30
910.361730.862211.262551.674502.31
920.391820.912251.282561.804512.32
970.47
Table 6 Umbrella samplings obtained by dopamine moving within D3R along the z+ axis
Fig 7 (o, a, b, c) Four pictures of the tracks along the z-axis for DOP to move from within D3R into the POPC phospholipid bilayer membrane on the main view and top view respectively; (A) PMF of the track along the z-axis for DOP to move
n D/nm n D/nm n D/nm n D/nm n D/nm
5 (o)01080.29149 (b)1.601722.12208 (c)2.39
80.051120.341501.841832.183532.42
320.111440.401511.911892.213602.48
550.161450.431571.941972.253842.51
770.211460.501641.992002.293972.53
810.23147 (a)0.921652.032012.334092.54
910.261481.171692.072042.374202.57
Table 7 Umbrella samplings obtained by dopamine moving within D3R along the z-axis
Fig 8 (o, a, b, c) Four pictures of the tracks along the z- axis for DOP to move from within D3R into the POPC phospholipid bilayer membrane on the main view and top view respectively; (A) PMF of the track along the z- axis for DOP to move
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