Homology Modeling And Molecular Dynamics Simulation Studies Of Dopamine D₄ Receptor

Dopamine receptors belong to a family of G protein-coupled receptor.It is well known that abnormal dopamine receptor signaling and dopaminergic nerve function are implicated in Parkinson’s disease,schizophrenia and several other diseases.In this thesis,we use dopamine D3 receptor(D3R)as a template to study an accurate structure of dopamine D4 receptor(D4R)by homology modeling method,because the sequence homology across transmembrane region between D3R and D4R is as high as 51.9%.The dopamine-D4R complex was obtained by using the Dock6 program.Based on the complex protein structure,molecular dynamics simulations were carried out within the POPC-cholesterol-water system for 300 ns using the Gromacs 4.5.3 program.Three samples of 100,200 and 300 ns were extracted from the 300 ns trajectory simulation file,and the binding energies were calculated using the MP2/6-31G(d,p)method,with the basis set superposition errors corrected using the Boys and Bernardi method.The obtained results show that the binding energy of dopamine to D4R protein is-123.00 kJ-mol"1,which is stronger than it to D3R protein.The active binding pocket is similar to it within D3R,surrounded by TM2,TM3,TM5,TM6 and TM7.The active residue sites are Asp080(TM2),Asp115(TM3),Tyr192(TM5),Phe410(TM6),His414(TM6),Tyr438(TM7),and they contribute about 78%of the binding energy.The active residue sites of D3R for dopamine are Asp117(TM3),Ser208(TM5),Phe269(TM6),His272(TM6)and Thr276(TM6),in which Asp117(TM3)and His272(TM6)are corresponding with Asp115(TM3)and His414(TM6)of D4R on the view of space respectively,and His272(D3R,TM6,Eb=-37.7 kJ-mol-1),His414(D4R,TM6,Eb＝-59.7kJ·mol-1)are the most important active site respectively.In our work,we have carried out the researches using the method by combining the molecular dynamics with quantum mechanics,the new method being efficient and accurate.The accurate structure of D4R from homology modeling and molecular dynamic simulation has an important significance in pathological research,drug development,diagnosis and clinical treatment.