Finding a Needle in a Haystack The Role of Electrostatics in Target Lipid Recognition by PH Domains 英文参考文献.docVIP

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Finding a Needle in a Haystack The Role of Electrostatics in Target Lipid Recognition by PH Domains 英文参考文献.doc

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Finding a Needle in a Haystack The Role of Electrostatics in Target Lipid Recognition by PH Domains 英文参考文献

FindingaNeedleinaHaystack:TheRoleofElectrostatics inTargetLipidRecognitionbyPHDomains CraigN.Lumb,MarkS.P.Sansom* DepartmentofBiochemistry,UniversityofOxford,Oxford,UnitedKingdom Abstract Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking.Thepleckstrinhomology(PH)domainisoneofthemostwidespread,bindingspecificallytophosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately20%anioniclipidswithinthecytoplasmicleafletoftheplasmamembrane.Weinvestigatethemechanismof suchrecognitionviaamultiscaleprocedurecombiningBrowniandynamics(BD)andmoleculardynamics(MD)simulations oftheGRP1PHdomaininteractingwithphosphatidylinositol(3,4,5)-trisphosphate(PI(3,4,5)P3).TheinteractionofGRP1-PH withPI(3,4,5)P3inazwitterionicbilayeriscomparedwiththeinteractioninbilayerscontainingdifferentlevelsofanionic ‘decoy’lipids.BDsimulationsrevealbothtranslationalandorientationalelectrostaticsteeringofthePHdomaintowardsthe PI(3,4,5)P3-containinganionicbilayersurface.Thereisapayoffbetweennon-PIPanioniclipidsattractingthePHdomainto the bilayer surface in a favourable orientation and their role as ‘decoys’, disrupting the interaction of GRP1-PH with the PI(3,4,5)P3molecule.Significantly,approximately20%anioniclipidinthecytoplasmicleafletofthebilayerisnearlyoptimal tobothenhanceorientationalsteeringandtolocaliseGRP1-PHproximaltothesurfaceofthemembranewithoutsacrificing itsabilitytolocatePI(3,4,5)P3 withinthebilayerplane.SubsequentMDsimulationsrevealbindingtoPI(3,4,5)P3 ,forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational frameworkwhichaddresseslipidrecognitionwithinacellmembraneenvironment,offeringalinkbetweenstructuraland cellbiologicalcharacterisation. Citation:LumbCN,SansomMSP(2012)FindingaNeedleinaHaystack:TheRoleofElectrostaticsinTargetLipidRecognitionbyPHDomains.PLoSComput