Mechanics of Channel Gating of the Nicotinic Acetylcholine Receptor 英文参考文献.docVIP

MechanicsofChannelGatingoftheNicotinic AcetylcholineReceptor Xinli Liu1,Yechun Xu2,Honglin Li2,Xicheng Wang1*,Hualiang Jiang2,3*,Francisco J.Barrantes4 1 Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, Dalian University of Technology, Dalian, Liaoning, China, 2DrugDiscoveryandDesignCenter,StateKeyLaboratoryofDrugResearch,ShanghaiInstituteofMateriaMedica,ChineseAcademyofSciences,Shanghai,China,3School ofPharmacy,EastChinaUniversityofScienceandTechnology,Shanghai,China,4UNESCOChairofBiophysicsMolecularNeurobiologyandInstitutodeInvestigaciones Bioqu?′micasdeBah?′aBlanca,Bah?′aBlanca,Argentina The nicotinic acetylcholine receptor (nAChR) is a key molecule involved in the propagation of signals in the central nervous system and peripheral synapses. Although numerous computational and experimental studies have been performedonthisreceptor,thestructuraldynamicsofthereceptorunderlyingthegatingmechanismisstillunclear. ToaddressthemechanicalfundamentalsofnAChRgating,bothconventionalmoleculardynamics(CMD)andsteered rotation molecular dynamics (SRMD) simulations have been conducted on the cryo-electron microscopy (cryo-EM) structureofnAChRembeddedinadipalmitoylphosphatidylcholine(DPPC)bilayerandwatermolecules.A30-nsCMD simulation revealed a collective motion amongst C-loops, M1, and M2 helices. The inward movement of C-loops accompanyingtheshrinkingofacetylcholine(ACh)bindingpocketsinducedaninwardandupwardmotionoftheouter b-sheetcomposedofb9andb10strands,whichinturncausesM1andM2toundergoanticlockwisemotionsaroundthe poreaxis.Rotationalmotionoftheentirereceptoraroundtheporeaxisandtwistingmotionsamongextracellular(EC), transmembrane(TM),andintracellularMAdomainswerealsodetectedbytheCMDsimulation.Moreover,M2helices undergo a local twisting motion synthesized by their bending vibration and rotation. The hinge of either twisting motion or bending vibration is located at the middle of M2, possibly the gate of the receptor