Molecular Dynamics Studies On Dopamine Molecular Channels Within Dopamine Fourth Receptor

Dopamine(DOP)is an important neurotransmitter.By effectively binding with its receptors after passing through the molecular channels to cause the structural conformation changes of the receptors,dopamine triggers the second messenger of neurotransmitter dopamine,and plays various functions in the manner of slow synaptic neurotransmitter transmission to transmit message,by regulating motor function,cognitive activity,reward mechanism and emotion,which is closely related to Parkinson's disease and schizophrenia.There are 5 subtypes of dopamine receptors.This thesis studied the dopamine molecular channels within the fourth dopamine receptor(D₄R)by employing the molecular dynamics method.We acquired the composite structure of D₄R-DOP by docking DOP molecule into the D₄R crystal structure.To obtain the refined composite structure,the D₄R-DOP structure was mounted into the POPC-H₂O membrane structure to perform molecular dynamics simulation under the protection of membrane environment for 50 ns(25 million steps).Based on this refined composite structure,we further studied the interaction between DOP and each amino acid residues within a 6(?)radius through quantum chemical method.The active amino acid residues were determined according to its binding energy,and they are Asp 115,Val 116,Thr 120,Glu188,Val 193,Ser 196,Ser 200 and His 414.These active residues form the active cavity structure for interacting with dopamine within D₄R.In this cavity structure,dopamine effectively binds with D₄R by an interaction energy of-74.37 k J·mol^-1.Only by effectively binding with D₄R in the active structure,can dopamine induce the conformation change of D₄R and perform its functions.The trajectories of DOP within D₄R along 6 directions–including 2 vertical directions(extracellular and intercellular directions)and 4 horizontal directions(between transmembrane domain)–were studied based on the refined structure of D₄R-DOP.We adopted the umbrella sampling method from the GROMACS program to determine the free energy changes along the trajectories,and further,to acquire the dopamine moving channels within D₄R.The results demonstrate that,to perform its function,the dopamine molecules located at the synaptic cleft,i.e.,the external end of D₄R,transmits through the dopamine functional channels along the trajectory about 3.5 nm long with the free energy change of-43.21 k J·mol^-1,which indicates that this is a spontaneous process.After performing its function,the dopamine molecules leave from D₄R through the dopamine protective channels along the 3 nm long trajectory between TM4 and TM5,and its free energy is increased by 117.48 k J·mol^-1.The energy needed in this process may be provided by the phosphorylation and dephosphorylation of G protein-coupled receptor or other key regulatory proteins,which results in the“on-state”and“off-state”of the D₄R structure for DOP to move in one direction along the channels in the structure.This thesis innovatively studied the dopamine molecular channels within D₄R,strengthened the scientific grounding of dopamine molecular channel theory by providing more new-found results.Based on the this theory,the researchers will gain more thoroughly understand of the essence and pathologies of Parkinson's Disease and schizophrenia,and the actual therapy will be assisted with the scientific theory.