Study On The Nicotinic Acetylcholine Receptor Homology Modeling And Molecular Dynamic Simulation

nAChRs are important drug targets as they mediate rapid chemical transmission of signal. Here the humanα7-nAChR and the Mouse muscle type nAChR were studied by homology modeling and molecular dynamic simulation. Result obtained from the investigation of theα7-nAChR homology models indicates that models built based on template 2QC1 are suitable for agonist screening, while they are not suitable for neurotoxin screening;α7-nAChR models built based on multiple templates 2QC1 and AChBP with closed C-loop conformation possess higher successful docking percentage for agonist screening than the corresponding models built based on single template 2QC1. In addition,α7-nAChR models built based on AChBP with open C-loop conformation is suitable for neurotoxin screening but not suitable for agonist screening. In summary, here a fact is further emphasized that homology modeling of the nAChR for agonist or neurotoxin screening should take the C-loop conformation state of the templates into consideration.Molecular dynamic simulation is performed on the Mouse muscle type nAChR model to study the ligand gated mechanism. The final result indicates the high resolution 2QC1 structure will not change its conformation considerably with the presence of the adjacent subunits in the pentamer; interprets the effect of the two water molecules in the hydrophilic cavity: the water molecules just like the nodes inter-bridging the residues to form the local network which may be related with the conformation transmission induced by the ligands; explains the reason why the side chains of the Tyr127 in the twoα1 subunits possess two kinds of conformations; interprets nAChR ligand gated mechanism by the interaction between antagonist-bungarotoxin and nAChR: when bungarotoxin interacts with nAChR, the C-loop of the receptor will be more open, which is responsible for the clockwise motion of the extracellular domain and the anticlockwise motion of the TM2 part, and the clockwise motion of the extracellular domain and the anticlockwise motion of the TM2 part will further induce the corresponding constriction of the channel in the extracellular domain and in the TM2 domain respectively.