General Anesthetics Predicted to Block the GLIC Pore with Micromolar Affinity 英文参考文献.docVIP

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General Anesthetics Predicted to Block the GLIC Pore with Micromolar Affinity 英文参考文献.doc

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General Anesthetics Predicted to Block the GLIC Pore with Micromolar Affinity 英文参考文献

GeneralAnestheticsPredictedtoBlocktheGLICPore withMicromolarAffinity DavidN.LeBard1.,Je′ro?meHe′nin2.,RodericG.Eckenhoff3,MichaelL.Klein1,GraceBrannigan4* 1Department of Chemistry and Institute for Computational Molecular Science, Temple University, Philadelphia, Pennsylvania, United States of America, 2Laboratoire d’Inge′nierie des Structures Macromole′culaires, CNRS and Aix-Marseille University, Marseille, France, 3Department of Anesthesiology and Critical Care, University of PennsylvaniaSchoolofMedicine,Philadelphia,Pennsylvania,UnitedStatesofAmerica,4DepartmentofPhysicsandCenterforComputationalandIntegrativeBiology, RutgersUniversity-Camden,Camden,NewJersey,UnitedStatesofAmerica Abstract Althoughgeneralanestheticsareknowntomodulatetheactivityofligand-gatedionchannelsintheCys-loopsuperfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However,todate,preciseaffinitydataforindividualsiteshasbeenchallengingtoobtainbybiophysicalmeans.Here,the likelyroleofporeblockinhibitionbythegeneralanestheticsisofluraneandpropofoloftheprokaryoticpentamericchannel GLICisinvestigatedbymolecularsimulations.Microscopicaffinitiesarecalculatedforbothsingleanddoubleoccupancy bindingofisofluraneandpropofoltotheGLICpore.Computationsarecarriedoutforanopen-poreconformationinwhich theporeisrestrainedtocrystallographicradius,andaclosed-poreconformationthatresultsfromunrestrainedmolecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for whichinhibitionbyisofluoraneandpropofolisobservedexperimentally.Calculatedaffinitiessuggestthatporeblockby propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancymayresultfrombindingofpropofoltoanallostericsiterecentlyidentifiedb