Comparison Between Dynamics Of G-Protein-Coupled Receptor CCR5in The Lipid And Water Environments

G-Protein-Coupled Receptor (GPCR), which is a superfamily of protein receptors, is characterized by seven transmembrane helices (7-TMH), and all its members are membrane protein. Since the membrane proteins are located within the lipid bilayer, their structures are difficult to be crystalized and resolved. As a result, almost all previous structural studies on GPCRs were implemented using the bioinformatic approaches. For example, the homology modeling method (the structural templates used are crystal structures of the bovine rhodopsin and bacteriorhodopsin) or ab initio prediction was used to construct the structural models of GPCR, and subsequently the methods of molecular dynamics simulation and essential dynamics analysis was employed to investigate their structural dynamic behaviors. However, almost all the previous simulation studies were performed in the water environment. Such a environment differs substantially from the real physiological environment where GPCR is located due to the lack of the the lipid bilayer and thereby would lead to different simulation results, thus making it difficult to explain the biological significance based on such results. In this thesis, the complete structural model for human C-C chemokine receptor type5(CCR5), which belongs to the GPCR family, has been constructed using the homology modeling method. The structural template used is the first solved crystal structure of CCR5. Subsequently, the CCR5structural model was embedded in a lipid bilayer model that is surrounded by SPC water molecule model. Based on this CCR5-lipid bilayer-solvent model, we further explored the technological route for molecular dynamics simulation of CCR5in the membrane environment. The success of molecular dynamics simulation on the CCR5-lipid bilayer-solvent model, in conjunction with simulation of CCR5-solvent model, allows us to compare the differences in dynamic properties of CCR5in the environments of lipid bilayer and water. The results revealed that, when compared with the simulation in water, the simulation performed under the lipid environment shows that the N-, C-termini and intracellular and extracellular loops of CCR5have higher conformational flexibility, larger solvent accessible surface area (SASA), and larger extensible volume, implying that the non-lipid-contacting regions in CCR5have richer conformational diversity; Although the transmembrane regions of CCR5was found to be more inflated in the membrane environment than in the water environment, they exhibited stronger rigidity in the membrane environment. Of paticular interest is that the Sit2(which is a pocket that has been found to accommodate the drug molecule maraviroc (MRV)) exhibits stronger rigidity in membrane environment than in water. It is possible that the high rigidity of Sit2is beneficial to maintenance of the pocket shape and therefore may lead to a more stable binding of the drug to the Sit2site. The above results indicate that the CCR5transmembrane regions has higher stability in membrane environment than in water, which may be caused by the high hydrophobic character of transmembrane helices. It is reasonable to believe that the CCR5dynamic properties deduced from the lipid environment simulation is closer to the real dynamics of physiological status than those from water environment simulation. Consequently, the relevant biological significance elicited from the results of membrane environment simulation will be more persuasive. The method established in this paper for molecular dynamics simulation of CCR5in the membrane environment lays a foundation for investigating the structure-function relationship of the membrane proteins.