Dopamine Molecular Channels Within D1 Receptor

Dopamine is a neurotransmitter in the mammalian brain.It stimulates dopamine receptors located in different regions of the brain to regulate various physiological functions of the central nervous system,such as participating in the regulation of body learning,memory,motivation,cognition,emotion,which is closely related to Parkinson's disease,schizophrenia,attention deficit hyperactivity syndrome,and drug addiction.At present,there are five distinct dopamine receptors:D1 receptor(D₁R),D2 receptor(D₂R),D3 receptor(D₃R),D4 receptor(D₄R)and D5 receptor(D₅R).The five dopamine receptors have high amino acid sequence homology each other.The D1 and D3 receptors share 39.72%homology within their seven transmembrane domains(TM).We used D3receptor(D₃R)as the template protein to construct the protein structure of D1 receptor(D₁R)by the homology modeling.The Dock6 program was used to dock the constructed D1 receptor(D₁R)with dopamine to obtain a binary composite structure.Then the binary composite structure was embedded into the POPC-H₂O structure,and by using Gromacs4.5.3 program to perform 50 ns molecular dynamics simulation on the structure.Based on the optimized composite structure,the B3LYP/6-31G(d,p)method in the Gaussian 09program was used to calculate the binding energy of the interaction between dopamine molecules and D1 receptor(D₁R),and determine the active amino acid residues.The results showed that there are seven active amino acid residues in D₁R,such as Asp49,Val52,Lys60,Asp82,Ser86,Trp218 and Asn256.The total binding energy between dopamine and D₁R is-120.64 k J?mol^-1,and the binding energy from the active amino acid residues with dopamine was-103.81 k J?mol^-1,accounting for 86.05%of the total binding energy.Based on the above optimized stable system,we used the umbrella sampling method in the Gromacs 4.5.3 program to calculate the moving trajectory and free energy potential surface for dopamine molecules within D₁R and to study the dopamine molecular channels within D₁R.The experimental results showed that the free energy for dopamine within D₁R moving along the Z-axis direction into the cell inside to be 234.75k J?mol^-1,and moving in the inverse direction of the Z+axis to be-93.99 k J?mol^-1.The protective molecular channels for dopamine moving along the direction of the cell bilayer membrane from D₁R are characterised by four directions:Y+,Y-,X+and X-,responsible for their free energies of 178.94,280.53,83.11 and 177.54 k J?mol^-1respectively.Considered the free energy values,it is found that the protective molecular channel for dopamine to leave from the gap between transmembrane helical TM2 and TM3 occupies a free energy of 83.11 k J?mol^-1.The free energy results(-93.99 k J?mol^-1)showed that dopamine could spontaneously pass through the functional channels within D₁R to play the function as a neurotransmitter.After playing the function,dopamine left the gap between transmembrane spiral TM2 and TM3 with the free energy of 83.11k J?mol^-1,to avoid the excessive functional role.If the dopamine functional channel is blocked by other large molecules,and the dopamine molecules cannot enter the dopamine functional channel,then it will lack the dopamine function,which cause Parkinson's disease.Since the essence of Parkinson's disease is the lack of dopamine function,keeping the dopamine functional pathway unblocked is an important treatment for Parkinson's disease.The channel for dopamine to leave from the dopamine receptor is the dopamine protective pathway.Dopamine,which has played the function,leaves dopamine receptors through the protective channel,thus to prevent dopamine from playing an excessive role,which is closely related to the pathology and treatment of schizophrenia.Therefore,by studying the dopamine molecular channels within D₁R,The obtained results can help further to reveal the mechanism of interaction between dopamine and its receptors,better to understand the pathology of Parkinson's disease,and promote the researches on the treatment of Parkinson's disease and new drugs.