Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations.docVIP

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Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations.doc

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Behavior of Solvent-Exposed Hydrophobic Groove in the Anti-Apoptotic Bcl-XL Protein Clues for Its Ability to Bind Diverse BH3 Ligands from MD Simulations

BehaviorofSolvent-ExposedHydrophobicGrooveinthe Anti-ApoptoticBcl-XLProtein:CluesforItsAbilitytoBind DiverseBH3LigandsfromMDSimulations DilrajLama.¤,VivekModi.,RamasubbuSankararamakrishnan* DepartmentofBiologicalSciencesBioengineering,IndianInstituteofTechnologyKanpur,Kanpur,India Abstract Bcl-XLisamemberofBcl-2familyofproteinsinvolvedintheregulationofintrinsicpathwayofapoptosis.Itsoverexpression inmanyhumancancersmakesitanimportanttargetforanti-cancerdrugs.Bcl-XLinteractswiththeBH3domainofseveral pro-apoptoticBcl-2partners.Thishelicalbundleproteinhasapronouncedhydrophobicgroovewhichacts asabinding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carriedouttoinvestigatethebehaviorofsolvent-exposedhydrophobicgroove.Thesimulationsusedeitheratwin-range cut-offorparticlemeshEwald(PME)schemetotreatlong-rangeinteractions.DestabilizationoftheBH3domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwindingofH2canberelatedtotheabilityofBcl-XLtobinddiverseBH3ligands.Thelossofhelicalcharactercanalsobe linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposureofBH3domainisacrucialeventbeforetheyformdimers.ThusunwindingofH2seemstobefunctionallyvery important.ThefourPMEsimulations,however,revealedastablehelixH2.ItispossiblethattheH2unfoldingmightoccurin PMEsimulationsatlongertimescales.Hydrophobicresiduesinthehydrophobicgrooveareinvolvedinstableinteractions amongthemselves.Thesolventaccessiblesurfaceareasofbulkyhydrophobicresiduesinthegroovearesignificantlyburied bytheloopLBconnectingthehelixH2andsubsequenthelix.Theseobservationshelptounderstandhowthehydrophobic patchinBcl-XLremainsstableinthesolvent-exposedstate.WesuggestthatboththedestabilizationofhelixH2andthe conformationalheterogeneityofloopLBareimportantfactorsforbindingofdiverseligandsinthehydrophob