Molecular_Docking

MolecularDockingS.ShahriarArabOverviewofthelectureIntroductiontomoleculardocking:DefinitionTypesSometechniquesPrograms“Protein-ProteinDockingwithSimultaneousOptimizationofRigid-bodyDisplacementandSide-chainConformations”JeffreyJ.Gray,StewartMoughon,ChuWang,OraSchueler-Furman,BrianKuhlman,CarolA.RohlandDavidBaker.J.Mol.Biol.(2003)331,281-299WhatisDocking?Dockingattemptstofindthe“best”matchingbetweentwomolecules…amoreseriousdefinition…Giventwobiologicalmoleculesdetermine:-Whetherthetwomolecules“interact”-Ifso,whatistheorientationthatmaximizesthe“interaction”whileminimizingthetotal“energy”ofthecomplex•Goal:TobeabletosearchadatabaseofmolecularstructuresandretrieveallmoleculesthatcaninteractwiththequerystructureWhyisdockingimportant?Itisofextremerelevanceincellularbiology,wherefunctionisaccomplishedbyproteinsinteractingwiththemselvesandwithothermolecularcomponentsItisthekeytorationaldrugdesign:Theresultsofdockingcanbeusedtofindinhibitorsforspecifictargetproteinsandthustodesignnewdrugs.ItisgainingimportanceasthenumberofproteinswhosestructureisknownincreasesExample:HIV-1ProteaseActiveSite(Aspartylgroups)Example:HIV-1ProteaseWhyisthisdifficult?Bothmoleculesareflexibleandmayaltereachother’sstructureastheyinteract:Hundredstothousandsofdegreesoffreedom(DOF)TotalpossibleconformationsareastronomicalTypesofDockingstudiesProtein-ProteinDockingBothmoleculesusuallyconsideredrigid6degreesoffreedomFirstapplystericconstraintstolimitsearchspaceandtheexamineenergeticsofpossiblebindingconformationsProtein-LigandDockingFlexibleligand,rigid-receptorSearchspacemuchlargerEitherreduceflexibleligandtorigidfragmentsconnectedbyoneorseveralhinges,orsearchtheconformationalspaceusingmonte-carlomethodsormoleculardynamicsSometechniques•Surfacerepresentation,thatefficientlyrepresentsthedockingsurfaceandidentifiestheregionsofinterest(cavitiesandprotrusions)ConnollysurfaceLenhofftechniqueKuntzetal.Clustered-SpheresAlphashapes•Surfacematchingthatmatchessurfacestooptimizeabindingscore:GeometricHashingSurfaceRepresentationEachatomicsphereisgiventhevanderWaalsradiusoftheatomRollingaProbeSphereovertheVanderWaalsSurfaceleadstotheSolventReentrantSurfaceorConnollysurfaceLenhofftechniqueComputesa“complementary”surfaceforthereceptorinsteadoftheConnollysurface,i.e.computespossiblepositionsfortheatomcentersoftheligandAtomcentersoftheligandvanderWaalssurfaceKuntzetal.Clustered-SpheresUsesclustered-spherestoidentifycavitiesonthereceptorandprotrusionsontheligandComputeasphereforeverypairofsurfacepoints,iandj,withthespherecenteronthenormalfrompointiRegionswheremanyspheresoverlapareeithercavities(onthereceptor)orprotrusions(ontheligand)ijAlphaShapesFormalizestheideaof“shape”In2Dan“edge”betweentwopointsis“alpha-exposed”ifthereexistsacircleofradiusalphasuchthatthetwopointslieonthesurfaceofthecircleandthecirclecontainsnootherpointsfromthepointsetAlphaShapes:ExampleAlpha=infinityAlpha=3.0ÅSurfaceMatchingFindthetransformation(rotation+translation)thatwillmaximizethenumberofmatchingsurfacepointsfromthereceptorandtheligand•Firstsatisfystericconstraints…Findthebestfitofthereceptorandligandusingonlygeometricalconstraints•…thenuseenergycalculationstorefinethedockingSelectthefitthathastheminimumenergyDockingprogramsDOCK(I.D.Kuntz,UCSF)AutoDock(ArthurOlson,TheScrippsResearchInstitute)AutoDockwasdesignedtodockflexibleligandsintoreceptorbindingsitesThestrongestfeatureofAutoDockistherangeofpowerfuloptimizationalgorithmsavailableRosettaDOCK(Baker,WashingtonUniv.,Gray,JohnsHopkinsUniv.)ItmodelsphysicalforcesandcreatesaverylargenumberofdecoysDOCKDOCKworksin5steps:Step1StartwithcrystalcoordinatesoftargetreceptorStep2GeneratemolecularsurfaceforreceptorStep3Generatespherestofilltheactivesiteofthereceptor:ThespheresbecomepotentiallocationsforligandatomsStep4Matching:Spherecentersarethenmatchedtotheligandatoms,todeterminepossibleorientationsfortheligandStep5Scoring:FindthetopscoringorientationDOCK:Example-HIV-1proteaseisthetargetreceptor-AspartylgroupsareitsactivesideDOCKDOCKworksin5steps:Step1StartwithcrystalcoordinatesoftargetreceptorStep2GeneratemolecularsurfaceforreceptorStep3Generatespherestofilltheactivesiteofthereceptor:ThespheresbecomepotentiallocationsforligandatomsStep4Matching:Spherecentersarethenmatchedtotheligandatoms,todeterminepossibleorientationsfortheligandStep5Scoring:FindthetopscoringorientationDOCK:Example-HIV-1proteaseisthetargetreceptor-AspartylgroupsareitsactivesideDOCKDOCKworksin5steps:Step1StartwithcrystalcoordinatesoftargetreceptorStep2GeneratemolecularsurfaceforreceptorStep3Generatespherestofilltheactivesiteofthereceptor:ThespheresbecomepotentiallocationsforligandatomsStep4Matching:Spherecentersarethenmatchedtotheligandatoms,todeterminepossibleorientationsfortheligandStep5Scoring:FindthetopscoringorientationDOCK:Example-HIV-1proteaseisthetargetreceptor-AspartylgroupsareitsactivesideDOCKDOCKworksin5steps:Step1StartwithcrystalcoordinatesoftargetreceptorStep2GeneratemolecularsurfaceforreceptorStep3Generatespherestofilltheactivesiteofthereceptor:Thespheresbecome