sequentiallyinfinidock

DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm1of659/18/20072:30PMDOCK6.
1UsersManualAuthors:P.
ThereseLang(UCSF)DemetriMoustakas(UCSF/Harvard)ScottBrozell(TheScrippsResearchInstitute)NoelCarrascal(SUNY-StonyBrook)SudiptoMukherjee(SUNY-StonyBrook)ScottPegg(UCSF)KaushikRaha(UCSF)DevleenaShivakumar(TheScrippsResearchInstitute)RobertRizzo(SUNY-StonyBrook)DavidCase(TheScrippsResearchInstitute)BrianShoichet(UCSF)IrwinKuntz(UCSF)Copyright2006-2007RegentsoftheUniversityofCaliforniaAllRightsReservedLastupdatedFebruary9,2007TableofContents1.
Introduction1.
1.
GeneralOverview1.
2.
WhatCanDOCKDoforYou1.
3.
Installation1.
4.
What'sNewinDOCK61.
5.
OverviewoftheDOCKSuiteofPrograms2.
DOCKDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm2of659/18/20072:30PM2.
1.
Overview2.
2.
History2.
3.
Command-lineArguments2.
4.
TheParameterParser2.
5.
LigandFileInput2.
6.
OrientingtheLigand2.
6.
1.
SphereMatching2.
6.
2.
CriticalPoints2.
6.
3.
ChemicalMatching2.
6.
4.
MacromolecularDocking2.
7.
LigandFlexibility2.
7.
1.
Anchor-and-Grow2.
7.
2.
IdentificationofRigidSegments2.
7.
3.
ManualSpecificationofNon-rotatableBonds2.
7.
4.
IdentificationofFlexibleLayers2.
7.
5.
PruningtheConformationSearchTree2.
7.
6.
InternalEnergyCalculation2.
7.
7.
TimeRequirements2.
8.
Scoring2.
8.
1.
BumpFilter2.
8.
2.
ContactScore2.
8.
3.
Grid-BasedScore2.
8.
4.
DOCK3.
5Score2.
8.
5.
ContinuousScore2.
8.
6.
ZouGB/SAScore2.
8.
7.
HawkinsGB/SAScore2.
8.
8.
PB/SAScore2.
8.
9.
AMBERScore2.
9.
MinimizationDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm3of659/18/20072:30PM2.
10.
ParameterFiles2.
10.
1.
AtomDefinitionRules2.
10.
2.
vdw.
defn2.
10.
3.
chem.
defn2.
10.
4.
chem_match.
tbl2.
10.
5.
flex.
defn2.
10.
6.
flex_drive.
tbl2.
11.
LigandFileOutput2.
12.
ParallelProcessing3.
Accessories3.
1.
Grid3.
1.
1.
Overview3.
1.
1.
BumpChecking3.
1.
2.
ContactScoring3.
1.
3.
EnergyScoring3.
2.
Docktools3.
2.
1.
Chemgrid3.
2.
1.
LigandDesolvation3.
2.
2.
OccupancyDesolvation3.
2.
3.
GridConversion3.
3.
Nchemgrids3.
4.
Sphgen3.
4.
1.
Overview3.
4.
2.
CriticalPoints3.
4.
3.
ChemicalMatching3.
4.
4.
Output3.
5.
Showbox3.
6.
Showsphere3.
7.
SphereSelectorDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm4of659/18/20072:30PM3.
8.
Antechamber4.
MolecularFileFormats4.
1.
TriposMOL2Format4.
2.
PDBFormat5.
ReferencesIntroductionRETURNTOTABLEOFCONTENTS1.
1.
GeneralOverviewDOCKaddressestheproblemof"docking"moleculestoeachother.
Ingeneral,"docking"istheidentificationofthelow-energybindingmodesofasmallmolecule,orligand,withintheactivesiteofamacromolecule,orreceptor,whosestructureisknown.
Acompoundthatinteractsstronglywith,orbinds,areceptorassociatedwithadiseasemayinhibititsfunctionandthusactasadrug.
Solvingthedockingproblemcomputationallyrequiresanaccuraterepresentationofthemolecularenergeticsaswellasanefficientalgorithmtosearchthepotentialbindingmodes.
Historically,theDOCKalgorithmaddressedrigidbodydockingusingageometricmatchingalgorithmtosuperimposetheligandontoanegativeimageofthebindingpocket.
Importantfeaturesthatimprovedthealgorithm'sabilitytofindthelowest-energybindingmode,includingforce-fieldbasedscoring,on-the-flyoptimization,animprovedmatchingalgorithmforrigidbodydockingandanalgorithmforflexibleliganddocking,havebeenaddedovertheyears.
FormoreinformationonpastversionsofDOCK,clickhere.
WiththereleaseofDOCK6,wecontinuetoimprovethealgorithm'sabilitytopredictbindingposesbyaddingnewfeatureslikeforce-fieldscoringenhancedbysolvationandreceptorflexibility.
FormoreinformationaboutthecurrentreleaseofDOCK,clickhere.
RETURNTOTABLEOFCONTENTS1.
2.
WhatCanDOCKDoforYouWeandothershaveusedDOCKforthefollowingapplications:predictbindingmodesofsmallmolecule-proteincomplexessearchdatabasesofligandsforcompoundsthatinhibitenzymeactivitysearchdatabasesofligandsforcompoundsthatbindaparticularproteinsearchdatabasesofligandsforcompoundsthatbindnucleicacidtargetsexaminepossiblebindingorientationsofprotein-proteinandprotein-DNAcomplexeshelpguidesyntheticeffortsbyexaminingsmallmoleculesthatarecomputationallyderivatizedmanymore.
.
.
RETURNTOTABLEOFCONTENTSDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm5of659/18/20072:30PM1.
3.
InstallationNOTEFORWINDOWSUSERS:DOCKanditsaccessoriesmustberunusingaLinux-likeenvironmentlikeCygwin(http://www.
cygwin.
com/).
Whenyouinstallyouremulator,makesuretoalsoinstallcompilers,unixshells,andperl(DevelforCygwin).
AllstepsbelowshouldbeperformedusingCygwinoranotherWindows-basedLinuxemulator.
(1)Decompressandextractfoldersusingthefollowingcommands:[user@dock~]tar-zxvfdock.
6.
1.
tar.
gz(2)Entertheinstallationdirectory[user@dock~]cddock6/install(3)ConfiguretheMakefilefortheappropriateoperatingsystem[user@dock~].
/configure[configurationfile]AUTHOR:ScottBrozellUSAGE:configure[-help][configurationfile]OPTIONS-help#emittheusagestatementconfigurationfile#inputfilecontainingoperatingsystemappropriatevariablesConfigurationFilesTargetgnugnu-stylecompilergnu.
parallelgnu-stylecompilerwithparallelprocessinglibrarycapabilitygnu.
pbsagnu-stylecompilerwithPB/SA(ZAPlibrary)capabilitygnu.
parallel.
pbsagnu-stylecompilerwithparallelprocessinglibraryandPB/SA(ZAPlibrary)capabilitiessgisgi-stylecompilersgi.
parallelsgi-stylecompilerwithparallelprocessinglibrarycapabilityDESCRIPTION:CreatetheDOCKconfigurationfile,config.
h,bycopyinganexistingconfigurationfilethatisselectedusingthearguments.
Wheninvokedwithoutarguments,printthisusagestatementandiftheconfigurationfileexiststhenprintitscreationstamp.
Someconfigurationfilesrequirethatenvironmentvariablesbedefined;theserequirementsarelistedinthefilesandemittedbyconfigure.
(4)OPTIONAL:Defineenvironmentvariables.
(i)DOCKwithparallelprocessingfunctionalityrequiresaMessagePassingInterface(MPI)library.
BecauseofthevagariesofMPIlibraries,buildingparallelDOCKhasmorepitfallsthaninstallingtheserialversion.
TheMPIlibrarymustbeinstalledandrunningonthesystemiftheparallelfeaturesofDOCKaretobeused.
Currently,theDOCKinstallationmechanismonlydirectlysupportstheMPICH2andMPICHimplementations.
TheMPICH2libraryisfreelyavailablefromDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm6of659/18/20072:30PMArgonneNationalLabs(http://www-unix.
mcs.
anl.
gov/mpi/mpich/).
OnceMPIisinstalled,definetheenvironmentvariableMPICH_HOMEtothetoplevelMPICH2directory.
WARNING:TheparallelconfigurationfileshavebeentailoredtoatypicalMPICH2build.
Linkingproblems,suchasundefinedreferencesandcannotfindlibbla_bla,canoccurduetoidiosyncrasiesintheMPIinstallation.
Onecorrectiveapproachistousemanuallinking;addtotheLIBSdefinitioninconfig.
hthelinkflags(-Land-l)fromthecommand:$MPICH_HOME/mpicc-show;ingeneral,theLIBSshouldcontainthoselinkflagsinthesameorder.
(ii)DOCKwithPB/SAscoringrequirestheOpenEyeZAPlibrary.
TheZAPlibrarycanbeobtainedfromOpenEye(http://www.
eyesopen.
com/).
OnceZAPisinstalled,definetheenvironmentvariableZAP_HOMEtothedirectorythatcontainstheZAPlibrary.
(5)BuildthedesiredDOCKexecutable(s)viaoneofthefollowingcommands:[user@dock~]makeall#buildsalltheDOCKprograms[user@dock~]makedock#buildsonlythedockprogram[user@dock~]makeutils#buildsonlytheaccessoryprograms(6)Testthebuiltexecutable(s)viathissequenceofcommands:[user@dock~]cdtest[user@dock~]makeclean[user@dock~]maketestThisdirectorycontainstheDOCKqualitycontrol(QC)suite.
Itproducespass/failresultsviafastregressiontests.
Thesuiteshouldcompleteinlessthantenminutes;un-passedtestsshouldbeexaminedtodeterminetheirsignificance.
Iffailuresoccurthenexaminetheoutputsviathecommand:[user@dock~]makecheckNOTE:Somefailuresarenotsignificant.
Forexample,differencesinthetailsoffloatingpointnumbersmaynotbesignificant.
Thesourcesofsuchdifferencesarefrequentlyplatformdependenciesfromcomputerhardware,operatingsystems,andcompilersthatimpactarithmeticprecisionandrandomnumbergenerators.
WeareworkingonincreasingDOCK'sresiliencetotheseissues.
Fornow,applycommonsenseandgoodjudgmenttodeterminethesignificanceofapossiblefailure.
Ifyouhaveproblemswithanyofthestepsabove,pleasecontactusatdock_bugs@dock.
compbio.
ucsf.
eduwithafulldescriptionofyourproblem.
RETURNTOTABLEOFCONTENTS1.
4.
What'sNewinDOCK6Version6.
0ThenewfeaturesofDOCK6include:additionalscoringoptionsduringminimization;DOCK3.
5scoring-includingDelphielectrostatics,ligandconformationalentropycorrections,liganddesolvation,receptordesolvation;Hawkins-Cramer-TruhlarGB/SAsolvationscoringwithoptionalsaltscreening;PB/SAsolvationscoring;AMBERscoring-includingreceptorflexibility;thefullAMBERDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm7of659/18/20072:30PMmolecularmechanicsscoringfunctionwithimplicitsolvent;conjugategradientminimizationandmoleculardynamicssimulationcapabilities.
Version6.
1ThenewlyaddedfeaturesfortheincrementalreleaseofDOCK6includeanewpruningalgorithmduringtheanchor-and-growalgorithm,adistance-basedmovableregionandamildlyperformanceoptimizednothingmovableregionforAMBERscore,cleaneroutputandmorecompleteoutputfilesforAMBERscore,theabilitytoperformrankingand/orclusteringonligandsbetweenprimaryandsecondaryscoring,andmoredynamicoutputwhensecondaryscoringisemployed.
RETURNTOTABLEOFCONTENTS1.
5.
OverviewoftheDOCKSuiteofPrograms1.
5.
1.
ProgramsTherelationshipbetweenthemainprogramsinthedocksuiteisdepictedinFigure1.
Theseroutineswillbedescribedbelow.
MainprogramsinDOCKsuiteTheprogramsphgenidentifiestheactivesite,andothersitesofinterest,andgeneratesthespherecentersthatfillthesite.
Ithasbeendescribedintheoriginalpaper(Kuntz,etal.
J.
Mol.
Biol.
1982).
Theprogramgridgeneratesthescoringgrids(Shoichet,etal.
J.
Comp.
Chem.
1992andMeng,etal.
J.
Comp.
Chem.
1992).
WithintheDOCKsuiteofprograms,theprogramDOCKmatchesspheres(generatedbysphgen)withligandatomsandusesscoringgrids(fromgrid)toevaluateligandorientations(Kuntz,etal.
J.
Mol.
Biol.
1982andShoichet,etal.
J.
Comp.
Chem.
1992).
ProgramDOCKalsominimizesenergybasedscores(Meng,etal.
Proteins.
1993).
1.
5.
2.
GeneralConceptsTheDOCKsuiteofprogramsisdesignedtofindfavorableorientationsofaligandina"receptor.
"Itcanbesubdividedinto(i)thoseprogramsrelateddirectlytodockingofligandsand(ii)accessoryprograms.
Welimitthediscussioninthissectiontoonlythoseprogramsandmethodsrelatedtodockingaligandinareceptor.
Atypicalreceptormightbeanenzymewithawell-definedactivesite,thoughanymacromoleculemaybeused(e.
g.
astructuralprotein,anucleicacidstrand,aDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm8of659/18/20072:30PM"true"receptor).
We'lluseanenzymeasanexampleintherestofthisdiscussion.
ThestartingpointofalldockingcalculationsisgenerallythecrystalorNMRstructureofanenzymefromanenzyme-ligandcomplex.
Theligandstructuremaybetakenfromthecrystalstructureoftheenzyme-ligandcomplexorfromadatabaseofcompounds,suchastheZINCdatabase(Irwin,et.
al.
J.
Chem.
Inf.
Model.
2005).
Theprimaryconsiderationinthedesignofourdockingprogramshasbeentodevelopmethodswhicharebothrapidandreasonablyaccurate.
Theseprogramscanbeseparatedfunctionallyintoroughlytwoparts,eachsomewhatindependentoftheother:(i)Routineswhichdeterminetheorientationofaligandrelativetothereceptorand(ii)Routineswhichevaluate(score)aligandorientation.
Thereisalotofflexibility.
YoucangenerateorientationsoutsideofDOCKandscorethemwiththeDOCKevaluationfunctions.
Alternatively,youcandevelopyourownscoringroutinestoreplacethefunctionssuppliedwithDOCK.
Theligandorientationinareceptorsiteisbrokendownintoaseriesofsteps,indifferentprograms.
First,apotentialsiteofinterestonthereceptorisidentified.
(Often,theactivesiteisthesiteofinterestandisknownapriori.
)Withinthissite,pointsareidentifiedwhereligandatomsmaybelocated.
AroutinefromtheDOCKsuiteofprogramsidentifiesthesepoints,calledspherecenters,bygeneratingasetofoverlappingsphereswhichfillthesite.
RatherthanusingDOCKtogeneratethesespherecenters,importantpositionswithintheactivesitemaybeidentifiedbysomeothermechanismandusedbyDOCKasspherecenters.
Forexample,thepositionsofatomsfromtheboundligandmaybeusedasthesespherecenters.
Or,agridmaybegeneratedwithinthesiteandeachgridpointmaybeconsideredasaspherecenter.
Ourspherecenters,however,attempttocaptureshapecharacteristicsoftheactivesite(orsiteofinterest)withaminimumnumberofpointsandwithoutthebiasofpreviouslyknownligandbindingmodes.
Toorientaligandwithintheactivesite,someofthespherecentersare"matched"withligandatoms.
Thatis,aspherecenteris"paired"withanligandatom.
Manysetsoftheseatom-spherepairsaregenerated,eachsetcontainingonlyasmallnumberofsphere-atompairs.
Inordertolimitthenumberofpossiblesetsofatom-spherepairs,alongestdistanceheuristicisused;(long)inter-spheredistancesareroughlyequaltothecorresponding(long)inter-atomicliganddistances.
Asetofatom-spherepairsisusedtocalculateanorientationoftheligandwithinthesiteofinterest.
Thesetofsphere-atompairswhichareusedtogenerateanorientationisoftenreferredtoasamatch.
Thetranslationvectorandrotationmatrixwhichminimizesthermsdof(transformed)ligandatomsandmatchingspherecentersofthesphere-atomsetarecalculatedandusedtoorienttheentireligandwithintheactivesite.
Theorientationoftheligandisevaluatedwithashapescoringfunctionand/orafunctionapproximatingtheligand-enzymebindingenergy.
Mostevaluationsaredoneon(scoring)gridsinordertominimizetheoverallcomputationaltime.
Ateachgridpoint,theenzymecontributionstothescorearestored.
Thatis,receptorcontributionstothescore,potentiallyrepetitiveandtimeconsuming,arecalculatedonlyonce;theappropriatetermsarethensimplyfetchedfrommemory.
Theligand-enzymebindingenergyistakentobeapproximatelythesumofthevanderWaalattractive,vanderWaaldispersive,andCoulombicelectrostaticenergies.
Approximationsaremadetotheusualmolecularmechanicsattractiveanddispersivetermsforuseonagrid.
Togeneratetheenergyscore,theligandatomtermsarecombinedwiththereceptortermsfromthenearestgridpoint,orcombinedwithreceptortermsfroma"virtual"gridpointwithinterpolatedreceptorvalues.
Thescoreisthesumofoverallligandatomsforthesecombinedterms.
Inthiscase,theenergyscoreisdeterminedbybothligandatomtypesandDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm9of659/18/20072:30PMligandatompositionsontheenergygrids.
Asafinalstep,intheenergyscoringscheme,theorientationoftheligandmaybevariedslightlytominimizetheenergyscore.
Thatis,aftertheinitialorientationandevaluation(scoring)oftheligand,asimplexminimizationisusedtolocatethenearestlocalenergyminimum.
Thespherecentersthemselvesaresimplyapproximationstopossibleatomlocations;theorientationsgeneratedbythesphere-atompairing,althoughreasonable,maynotbeminimalinenergy.
1.
5.
3.
SpecificConcepts(A)SphereCentersSpheresaregeneratedtofillthetargetsite.
Thespherecentersareputativeligandatompositions.
Theiruseisanattempttolimittheenormousnumberofpossibleorientationswithintheactivesite.
Likeligandatoms,thesespherestouchthesurfaceofthemoleculeanddonotintersectthemolecule.
Thespheresareallowedtointersectotherspheres;i.
e.
theyhavevolumeswhichoverlap.
Eachsphereisrepresentedbythecoordinatesofitscenteranditsradius.
Onlythecoordinatesofthespherecentersareusedtoorientligandswithintheactivesite(seeabove).
Sphereradiiareusedinclustering.
Thenumberoforientationsoftheligandinfreespaceisvast.
Thenumberoforientationspossiblefromallsetsofsphere-atompairingsissmallerbutstilllargeandcannotbegeneratedandevaluated(scored)inareasonablelengthoftime.
Consequently,variousfiltersareusedtoeliminatefromconsideration,beforeevaluation,setsofsphere-atomspairs,whichwillgeneratepoorlyscoringorientations.
Thatis,onlyasmallsubsetofthenumberofpossibleligandorientationsareactuallygeneratedandscored.
Thedistancetoleranceisonefilter.
Sphere"coloring"andidentificationof"critical"spheresareotherfilters.
Sphere-spheredistancesarecomparedtoatom-atomdistances.
Setsofsphere-atompairsaregeneratedinthefollowingmanner:sphereiispairedwithatomIifandonlyifforeveryspherejinthesetandforeveryatomJintheset,wheredijisthedistancebetweensphereiandspherej,dIJisthedistancebetweenatomIandatomJ,andepsilonisasomewhatsmalluser-definedvalue.
(B)ChemicalMatchingDOCKspheresaregeneratedwithoutregardtothechemicalpropertiesofthenearbyreceptoratoms.
Sphere"chemicalmatching"or"coloring"associatesachemicalpropertytospheresandasphereofone"color"canonlybematchedwithaligandatomofcomplementarycolor.
Thesechemicalpropertiesmaybethingssuchas"hydrogen-bonddonor,""hydrogen-bondacceptor,""hydrophobe,""electro-positive,""electro-negative,""neutral,"etc.
Neitherthecolorsthemselves,northecomplementarityofthecolors,aredeterminedbytheDOCKsuiteofprograms;DOCKsimplyusestheselabels.
Withtheinclusionofcoloring,onlyligandatomswiththeappropriatechemicalpropertiesarematchedtothecomplementarycoloredspheres.
Itisprobablymorelikely,then,thattheorientationgeneratedwillproduceafavorablescore.
Conversely,byexcludingcoloredspheresfrompairingwithcertainligandatoms,thenumberof(probably)unfavorableorientationswhicharegeneratedandevaluatedcanbereduced.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm10of659/18/20072:30PMNotethatrequiringcomplementarityinmatchingdoesnotmeanthatallligandatomswilllieinchemicallycomplementaryregionsoftheenzyme.
Rather,onlythoseligandatoms,whenpairedwithacoloredspherewhichispartofthesphere-atommatch,willbeguaranteedtobeinthechemicallycomplementaryregionoftheenzyme(providedchiralityofthespheresisthesameasthatofthematchingligandatoms).
(C)CriticalPointsThe"criticalpoint"filterrequiresthatcertainspheresbepartofthesetofsphere-atompairsusedtoorienttheligand(DesJarlais,etal.
J.
Comput-AidedMolec.
Design.
1994).
Designatingspheresascriticalpointsforcestheligandtohaveatleastoneatominthatareaoftheenzyme,wherethatsphereislocated.
Thisfiltermaybeuseful,forexample,whenitisknownthataligandmustoccupyaparticularareaofanactivesite.
Thisfilterremovesfromconsiderationanyorientationthatdoesnotguaranteeatleastoneligandatomincriticalareasoftheenzyme(providedchiralityofthespheresisthesameasthatofthematchingligandatom).
(D)BumpFilterAfteraligandisorientedwithintheactivesite,theorientationisevaluated.
Inanattempttoreducethetotalcomputationaltime,aftertheligandisorientedinthesite,itispossibletofirstcheckwhetherornotligandatomsoccupyspacealreadyoccupiedbythereceptor.
Iftoomanyofsuch"bumps"arefound,thentheligandislikelytointersectthereceptorevenafterminimization;consequently,theligandorientationisdiscardedbeforeevaluation.
RETURNTOTABLEOFCONTENTSDOCKRETURNTOTABLEOFCONTENTS2.
1.
OverviewThissectionisintendedasareferencemanualforthefeaturesoftheDOCKSuiteofPrograms.
ItisintendedtogiveanoverviewoftheideaswhichformthebasisoftheDOCKsuiteofprogramsandtodetailtheavailableuserparameters.
ItisnotintendedtobeasubstituteforallthepaperswrittenonDOCK.
Ingeneral,thisdocumentisgearedtowardstheexperienceduserandintroducesnewfeaturesandconceptsinversion6.
IfyouarenewtoDOCK,westronglyrecommendyoulookatthetutorialsontheDOCKwebsiteathttp://dock.
compbio.
ucsf.
edu/DOCK_6/index.
htm,whichgointomuchgreaterpracticaldetail.
RETURNTOTABLEOFCONTENTS2.
2.
HistoryVersion1.
0/1.
1Authors:RobertSheridan,ReneeDesJarlais,IrwinKuntzDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm11of659/18/20072:30PMTheprogramDOCKisanautomaticprocedurefordockingamoleculeintoareceptorsite.
Thereceptorsiteischaracterizedbycenters,whichmaycomefromSPHGENoranyothersource.
Themoleculebeingdockedischaracterizedbyligandcenters,whichmaybeitsnon-hydrogenatomsorvolume-fillingspherescalculatedinSPHGEN.
Theligandcentersandreceptorcentersarematchedbasedoncomparisonofligand-center/ligand-centerandreceptor-center/receptor-centerdistances.
Setsofligandcentersmatchsetsofreceptorcentersifalltheinternaldistancesmatch,withinavalueofdistance_tolerance.
Ligand-receptorpairsareaddedtothesetuntilatleastnodes_minimumpairshavebeenfound.
Atleastthreepairsmustbefoundtouniquelydeterminearotation/translationmatrixthatwillorienttheligandinthereceptorsite.
Aleast-squaresfittingprocedureisused(Ferro,etalAct.
Cryst.
A.
1977.
).
Onceanorientationhasbeenfound,itisevaluatedbyanyofseveralscoringfunctions.
DOCKmaybeusedtoexplorethebindingmodesofanindividualmolecule,orbeusedtoscreenadatabaseofmoleculestoidentifypotentialligands.
Version2.
0Authors:BrianShoichet,DaleBodian,IrwinKuntzDOCKversion2.
0waswrittentogivetheusergreatercontroloverthethoroughnessofthematchingprocedure,andthusoverthenumberoforientationsfoundandtheCPUtimerequired(Shoichet,etal.
J.
Comp.
Chem.
1992).
Inaddition,certainalgorithmicshortcomingsofearlierversionswereovercome.
Versions2.
0andhigherareparticularlyusefulformacromoleculardocking(Shoichet,etalJ.
Mol.
Biol.
1991)andapplicationswhichdemanddetailedexplorationofligandbindingmodes.
Inthesecases,usersareencouragedtorunCLUSTERinconjunctionwithSPHGENandDOCK.
Toallowforgreatercontroloversearchesoforientationspace,theligandandreceptorcentersarepre-organizedaccordingtotheirinternaldistances.
Startingwithanygivencenter,alltheothercentersarepresortedinto"bins"basedontheirdistancetothefirstcenter.
Allcentersaretriedinturnas"first"positions,andallthepointsinabinwhichhasbeenchosenformatchingaretriedsequentially.
Ligandandreceptorbinsarechosenformatchingwhentheyhavethesamedistancelimitsfromtheirrespective"first"points.
Thenumberofcentersineachbindetermineshowmanysetsofpointsinthereceptorandtheligandwillultimatelybecompared.
Ingeneral,thewiderthebins,thegreaterthenumberoforientationsgenerated.
Thus,thethoroughnessofthesearchisunderusercontrol.
Version3.
0Authors:ElaineMeng,BrianShoichet,IrwinKuntzVersion3.
0retainedthematchingfeaturesofversion2.
0,andintroducedoptionsforscoring(Meng,etal.
J.
Comp.
Chem.
,1992).
Besidesthesimplecontactscoresmentionedabove,onecanalsoobtainmolecularmechanicsinteractionenergiesusinggridfilescalculatedbyCHEMGRID(whichisnowsupersededbyGRIDinversion4.
0).
Moreinformationabouttheligandandreceptormoleculesisrequiredtoperformthesehigher-levelkindsofscoring.
Pointchargesonthereceptorandligandatomsareneededforelectrostaticscoring,andatom-typeinformationisneededforthevanderWaalsportionoftheforcefieldscore.
Inputformats(someofthemnewinversion3.
5)arediscussedinvariouspartsofthedocumentation;oneexampleofa"completeformat"(includingpointchargesandatomtypeinformation)isSYBYLMOL2format.
ParameterizationofthereceptorisdiscussedinthedocumentationforCHEMGRID.
InDOCK,ligandparametersarereadinalongwiththecoordinates;inputformatsaredescribedbelow.
Currently,theoptionsare:contactscoringonly,contactscoringplusDelphielectrostaticscoring,andcontactscoringplusforcefieldscoring.
Atom-typeinformationandpointchargesarenotrequiredforcontactscoringonly.
Version3.
5DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm12of659/18/20072:30PMAuthors:MikeConnolly,DanielGschwend,AndyGood,ConnieOshiro,IrwinKuntzVersion3.
5addedseveralfeatures:scoreoptimization,degeneracychecking,chemicalmatchingandcriticalclustering.
Version4.
0Authors:ToddEwing,IrwinKuntzVersion4.
0wasamajorrewriteandupdateofDOCK.
Anewmatchingenginewasdevelopedwhichismorerobust,efficient,andeasiertouse(Ewing,etal.
J.
Comput.
Chem.
1997).
Orientationalsamplingcannowbecontrolleddirectlybyspecifyingthenumberofdesiredorientations.
Additionalfeaturesincludechemicalscoring,chemicalscreening,andligandflexibility.
Version5.
0-5.
4Authors:DemetriMoustakas,P.
ThereseLang,ScottPegg,ScottBrozell,IrwinKuntzVersion5wasrewritteninC++inamodularformat,whichallowsforeasyimplementationofnewscoringfunctions,samplingmethodsandanalysistools(Moustakas,etal,2006).
AdditionalnewfeaturesincludeMPIparallelization,exhaustiveorientationsearching,improvedconformationsearching,GB/SAsolvationscoring,andpost-screeningposeclustering.
(Zou,etal.
J.
Am.
Chem.
Soc.
,1999)Version6.
0-6.
1DOCK6isanextensionoftheDOCK5codebase.
ItincludestheimplementationofHawkins-Cramer-TruhlarGB/SAsolvationscoringwithsaltscreeningandPB/SAsolvationscoringthroughOpenEye'sZapLibrary.
Additionalflexibilityhasbeenaddedtoscoringoptionsduringminimization.
ThenewcodealsoincorporatesDOCKversion3.
5.
54scoringfeatureslikeDelphielectrostatics,liganddesolvation,andreceptordesolvation.
Finally,DOCK6introducesnewcodethatallowsaccesstotheNABlibraryoffunctionssuchasreceptorflexibility,thefullAMBERmolecularmechanicsscoringfunctionwithimplicitsolvent,conjugategradientminimization,andmoleculardynamicssimulationcapabilities.
RETURNTOTABLEOFCONTENTS2.
3.
Command-lineArgumentsDOCKmustberuncommandlinefromastandardunixshell.
Itreadsaparameterfilecontainingfield/valuepairsusingthefollowingcommand:USAGE:dock6-idock.
in[-odock.
out][-v]DESCRIPTION:DOCKmaybeexecutedineitherinteractiveorbatchmode,dependingonwhetheroutputiswrittentoafile.
Ininteractivemode,theuserisrequestedonlyforparametersrelevanttotheparticularrunanddefaultvaluesareprovided.
Thismodeisrecommendedfortheinitialconstructionoftheinputfileandforshortcalculations.
Inbatchmode,inputparametersarereadinfromtheinputfileandalloutputiswrittentotheoutputfile.
Thismodeisrecommendedforlongcalculationsonceaninputfilehasbeengeneratedinteractively.
OPTIONS-idock.
in#inputfilecontaininguser-definedparameters-help#emittheusagestatement.
-v#verbosityflagthatprintsadditionalinformationandwarningsforscoringfunctionsDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm13of659/18/20072:30PM-odock.
out#outputfilecontainingtheparametersusedinthecalculation,summaryinformationforeachmoleculedocked,andallwarningmessagesInteractivemodeUSAGE:dock6-idock.
inDESCRIPTION:Whenlaunchedthisway,DOCKwillextractallrelevantparametersfromdock.
in(oranyfilesuppliedbytheuser).
Ifadditionalparametersareneeded(orifthedock.
infileisnon-existentorempty),DOCKwillrequestthemoneatatimefromtheuser.
Reasonabledefaultvaluesarepresented.
Anyparameterssuppliedbytheuserwillbeautomaticallyappendedtothedock.
infile.
Iftheuserwouldliketochangeanypreviouslyenteredvalues,theusercaneditinthedock.
infileusingatexteditor.
BatchmodeUSAGE:dock6-idock.
in-odock.
outDESCRIPTION:Whenlaunchedinthisway,DOCKwillruninbatchmode,extractingallrelevantparametersfromdock.
in(oranyfilesuppliedbytheuser)andwillwriteoutalloutputtodock.
out(oranyfilesuppliedbytheuser).
Ifanyparametersaremissingorincorrect,thenexecutionwillhaltandanappropriateerrormessagewillbereportedindock.
out.
ParallelDOCKUSAGE:mpirun[-machinefilemachfile][-np#_of_proc]dock6.
mpi-idock.
in-odock.
out[-v]DESCRIPTION:IfyouhavecompiledDOCKforparallelprocessing(seeInstallation),DOCKcanberuninparallel.
ParallelzationissetuptohaveasingleMasternodewiththeremainingnodesactasslaves.
TheMasternodeperformsfileprocessingandinput/output,whereastheslavesperformtheactualcalculations.
Ifnp=1,thecodedefaultstonon-MPIbehavior.
Asaresult,therewillbeminimaldifferenceinperformancebetween1and2processors.
Improvedperformancewillonlybecomeevidentwithmorethan2nodes.
ADDITIONALOPTIONS-machinefile#simpletextfilecontainingthenamesofthecomputers(nodes)tobeused-np#specifiesthenumberofprocessorswhichtypicallyisthesameasthenumberoflinesinthemachinefilePB/SADOCKUSAGE:dock6.
pbsa-idock.
in[-odock.
out][-v]DESCRIPTION:IfyouhavecompiledDOCKforusewiththeZAPlibrary(seeInstallation),DOCKcanberunusingtheZAPPB/SAscoringfunction.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm14of659/18/20072:30PMRETURNTOTABLEOFCONTENTS2.
4.
TheParameterParserInInteractiveMode,dockwilldynamicallyasktheusertoentertheappropriateuserparameters.
Thegenericformatforthequestionsis:parameter_name[defaultvalue](legalvalues):Theparameterparserrequiresthatthevaluesenteredforaparameterexactlymatchoneofthelegalvalues.
Forexample:ExampleA:program_location[Hello_World!
]():ExampleB:#_red_balloons[99]():ExampleC:glass_status[half_full](half_fullhalf_empty):InExampleA,theparameter"program_location"canbeassignedanystringvalue,andinExampleB,theparameter"#_red_balloons"canbeassignedanyintegervalue.
However,inExampleC,theparametervalue"glass_status"canonlybeassignedthestrings"half_full"or"half_empty".
Ifnoparameterareassignedbytheuser,thedefaultvalue--inbrackets--willbeused.
InBatchMode,allparametersinthedock.
infile,mustbe:parameter_namevalueNotethattheparameter_nameandcorrespondingvalueneedtobeseparatedbywhitespaceoratab.
RETURNTOTABLEOFCONTENTS2.
5.
LigandFileInputBeforeyoucandockaligand,youwillneedatomtypesandchargesforeveryatomintheligand.
Currently,DOCKonlyreadstheTriposMOL2format.
Forasingleligand(orseveralligands),youcanuseChimeraincombinationwithantechambertoprepareaMOL2filefortheligand(seeStructurePreparationTutorial)orvariousothervisualizationpackages.
Duringthedockingprocedure,ligandsarereadinfromasingleMOL2ormulti-MOL2file.
AtomandbondtypesareassignedusingtheDOCK4atom/bondtypingparameterfiles.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
MoleculeLibraryParametersligand_atom_file[database.
mol2](string):#Theligandinputfilenamelimit_max_ligands[no](yes,no):#Limitthenumberofligandstobereadinfromalibrarymax_ligands[1000]:DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm15of659/18/20072:30PM#maximumnumberofligandsthatwillbereadinfromalibraryskip_molecule[no](yes,no):#Skipsomenumberofmoleculesatthebeginningofalibraryinitial_skip[0](int):#Thenumberofmoleculestoskipoveratthebeginningofalibraryread_mol_solvation[no](yes,no):#Flagtoreadatomicdesolvationinformationfromligandfilecalculate_rmsd[no](yes,no):#FlagtoperformanRMSDcalculationbetweenthefinalmoleculeposeanditsinitial#structure.
use_rmsd_reference_mol[no](yes,no):#SpecifyalternativegeometriclocationforreferencestructureforRMSD#calculationrmsd_reference_filename[ligand_rmsd.
mol2](string):#Filecontainingalternativegeometriclocationforreferencestructurefor#RMSDcalculationRETURNTOTABLEOFCONTENTS2.
6.
OrientingtheLigand2.
6.
1.
SphereMatchingTherigidbodyorientingcodeiswrittenasadirectimplementationoftheisomorphoussubgraphmatchingmethodofCrippenandKuhl(Kuhl,etal.
J.
Comput.
Chem.
1984).
Allreceptorspherepairsandatomcenterpairsareconsideredforinclusioninamatchingclique.
Thisismorecomputationallydemandingthanthecliquematchingalgorithmimplementedinpreviousversionsthatusedadistancebinningalgorithmtorestrictthecliquesearch,inwhichpairsofspheresandatomcenterswerebinnedbydistance.
Onlyspherepairsandcenterpairsthatwerewithinthesamedistancebinwereconsideredaspotentialmatches(Ewing,etal.
J.
Comput.
Chem.
1997).
Thecliquematchingimplementationavoidsbinboundariesthatpreventsomereceptorsphereandligandatompairsfrommatching,and,asaresult,itcanfindgoodmatchesmissedbypreviousversionsofDOCK.
Therigidbodyrotationcodehasalsobeencorrectedtoavoidasingularitythatoccurredifthespheresinthematchlaywithinthesameplane.
Therearetwotypesofligandorientationcurrentlyavailable:(1)AutomatedMatching—Specifythenumberoforientations,andDOCKwillgeneratematchesuntilenoughorientationspassingthebumpfilterhavebeenformed.
Matchesareformedbestfirst,withrespecttothedifferenceintheligandandsitepointinternaldistances.
(2)ManualMatching—Specifythedistanceandnodeparameters,andDOCKwillgenerateallthematcheswhichsatisfythem.
Thenumberoforientationsscoredisequaltothetotalmatchesminustheorientationsdiscardedbytheuserappliedfilters.
Multipleorientationsmaybewrittenoutforeachmoleculeusingthewrite_orientationsparameter(seeLigandFileOutput),otherwiseonlythebestorientationisrecorded.
RETURNTOTABLEOFCONTENTSDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm16of659/18/20072:30PM2.
6.
2.
CriticalPointsThecritical_pointsfeatureisusedtofocustheorientationsearchintoasubsiteofthereceptoractivesite(DesJarlais,etal.
J.
Comput-AidedMolec.
Design.
1994andMiller,etalJ.
Comput.
AidedMol.
Design.
1994).
Forexample,identifyingmoleculesthatinteractwithcatalyticresiduesmightbeofchiefinterest.
Anynumberofpointsmaybeidentifiedascritical(seeCriticalPointsinformationonlabelingspheres),andanynumberofgroupingsofthesepointsmaybeidentified.
Analternativetousingcriticalpointsistodiscardallsitepointsthataresomedistanceawayfromthesubsiteofinterest,whileretainingenoughsitepointstodefineuniqueligandorientations.
Thisfeaturecanbehighlyeffectiveatreducingmatchingbyfive-foldormore.
Itisparticularlyusefultoalsoassignchemicallabelstothecriticalpointstofurtherfocussampling.
RETURNTOTABLEOFCONTENTS2.
6.
3.
ChemicalMatchingThechemical_matchingfeatureisusedtoincorporateinformationaboutthechemicalcomplementarityofaligandorientationintothematchingprocess.
Inthisfeature,chemicallabelsareassignedtositepoints(seeChemicalMatchingforinformationonlabelingspheres)andligandatoms(seeLigandFileInput)(Kuhl,etal.
J.
Comput.
Chem.
1984).
Thesitepointlabelsarebasedonthelocalreceptorenvironment.
Theligandatomlabelsarebasedonuser-adjustablechemicalfunctionalityrules.
Theselabelingrulesareidentifiedwiththechemical_defn_fileparameterandresideinaneditablefile(seechem.
defn).
Anodeinamatchwillproduceanunfavorableinteractioniftheatomandsitepointcomponentshavelabelswhichviolateachemicalmatchrule.
Thechemicalmatchingrulesareidentifiedwiththechemical_match_fileparameterandresideinaneditablefile(seechem_match.
tbl).
Ifamatchwillproduceunfavorableinteractions,thenthematchisdiscarded.
Thespeed-upfromthistechniquedependshowextensivelysitepointshavebeenlabeledandthestringencyofthematchrules,butanimprovementoftwo-foldormorecanbeexpected.
RETURNTOTABLEOFCONTENTS2.
6.
4.
MacromolecularDockingAlthoughDOCKistypicallyusedtoprocesssmallligandmolecules,itcanbeusedtostudytheinteractionsofmacromoleculareigands.
Thechiefdifferenceinprotocolisthattousethematch_receptor_sitesprocedurefortheorientationsearch,specialligandcentersmustbeusedtorepresenttheligand.
Thisissignaledbysettingtheligand_centersparameter.
Theligandcentersmaybeconstructedbysphgenandmustresideinafileidentifiedwiththeligand_center_fileparameter.
SeeShoichet,etal.
J.
Mol.
Biol.
1991forexamplesanddiscussionofmacromoleculardocking.
RETURNTOTABLEOFCONTENTSNOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm17of659/18/20072:30PMOrientLigandParametersorient_ligand[yes](yes,no):#Flagtoorientligandtospheresautomated_matching[yes](yes,no):#Flagtoperformautomatedmatchinginsteadofmanualmatching(Ifautomated_matching=no,thenmanual_matchingisused)distance_tolerence[0.
25](float):#Thetoleranceinangstromswithinwhichapairofspheresisconsideredequivalentto#apairofcentersdistance_minimum[2.
0](float):#Theshortestdistanceallowedbetween2spheres(anyspherepairwithashorter#distanceisdisregarded)nodes_minimum[3](int):#Theminimumnumberofnodesinacliquenodes_maximum[10](int):#Themaximumnumberofnodesinacliquereceptor_site_file[receptor.
sph](string):#Thefilecontainingthereceptorspheresmax_orientations[500](int):#Themaximumnumberoforientationsthatwillbecycledthroughcritical_points[no](yes,no):#Flagtousecriticalpointspherelabelingtotargetorientationstoparticularsphereschemical_matching[no](yes,no):#Flagtousechemicalcoloringofspherestomatchchemicallabelsonligandatomschem_match_tbl[chem_match.
tbl](string):#Filedefiningthelegalchemicaltypematches/pairingsuse_ligand_spheres[no](yes/no):#Flagtoenableaspherefilerepresentingligandheavyatomstobeusedtoorienttheligand#Typicallyusedformacromoleculardockingligand_sphere_file[ligand.
sph](string):#ThefilecontainingthereceptorspheresRETURNTOTABLEOFCONTENTS2.
7.
LigandFlexibility2.
7.
1.
Anchor-and-GrowTheprocessofdockingamoleculeusingtheanchor-firststrategyisshownintheWorkflowforAnchor-and-GrowAlgorithm.
First,thelargestrigidsubstructureoftheligand(anchor)isidentified(seeIdentificationofRigidSegments)andrigidlyorientedintheactivesite(orientation)bymatchingitsheavyatomscenterstothereceptorspherecenters(seeOrientingtheLigand).
Theanchororientationsareevaluatedandoptimizedusingthescoringfunction(seeScoring)andtheenergyminimizer(seeMinimization).
Theorientationsarethenrankedaccordingtotheirscore,spatiallyclusteredbyheavyatomrootmeansquareddeviation(RMSD),andpruned(seePruningtheConformationSearchTree).
Next,theremainingflexibleportionoftheligand(seeIdentificationofFlexibleLayers)isbuiltontothebestanchororientationswithinthecontextofthereceptor(grow).
Itisassumedthattheshapeofthebindingsitewillhelprestrictthesamplingofligandconformationstothosethataremostrelevantforthereceptorgeometry.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm18of659/18/20072:30PMWorkflowforAnchor-and-GrowAlgorithmTheconformationofaflexiblemoleculemaybesearchedorrelaxedusingtheflexible_ligandoption.
Onlythetorsionanglesaremodified,notthebondlengthsorangles.
Therefore,theinputgeometryofthemoleculeneedstobeofgoodquality.
AstructuregeneratedbyZINCissufficient.
Thetorsionanglepositionsresideinaneditablefile(seeflex_drive.
tblonpage111)whichisidentifiedwiththeflex_drive_fileparameter.
Internalclashesaredetectedduringthetorsiondrivesearchbasedontheclash_overlaporinternal_energyparameters,whichareindependentofscoringfunction.
RETURNTOTABLEOFCONTENTS2.
7.
2.
IdentificationofRigidSegmentsAflexiblemoleculeistreatedasacollectionofrigidsegments.
Eachsegmentcontainsthelargestsetofadjacentatomsseparatedbynon-rotatablebonds.
Segmentsareseparatedbyrotatablebonds.
Thefirststepinsegmentationisringidentification.
Allbondswithinmolecularringsaretreatedasrigid.
Thisclassificationschemeisafirst-orderapproximationofDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm19of659/18/20072:30PMmolecularflexibility,sincesomeamountofflexibilitycanexistinnon-aromaticrings.
Totreatsuchphenomenonassugarpuckeringandchair-boathexaneconformations,theuserwillneedtosupplyeachringconformationasaseparateinputmolecule.
Additionalbondsmaybespecifiedasrigidbytheuser(seeManualSpecificationofNon-rotatableBonds).
IdentificationofRigidAnchorandFlexibleBondsThesecondstepisflexiblebondidentification.
Eachflexiblebondisassociatedwithalabeldefinedinaneditablefile(seeflex.
defn).
Theparameterfileisidentifiedwiththeflex_definition_fileparameter.
Eachlabelinthefilecontainsadefinitionbasedontheatomtypes(andchemicalenvironment)ofthebondedatoms.
Eachlabelisalsoflaggedasminimizable.
Typically,bondswithsomedegreeofdoublebondcharacterareexcludedfromminimizationsothatplanarityispreserved.
Eachlabelisalsoassociatedwithasetofpreferredtorsionpositions.
Thelocationofeachflexiblebondisusedtopartitionthemoleculeintorigidsegments.
Asegmentisthelargestlocalsetofatomsthatcontainsonlynon-flexiblebonds.
RETURNTOTABLEOFCONTENTS2.
7.
3.
ManualSpecificationofNon-rotatableBondsTheusercanspecifyadditionalbondstobenon-rotatable,tosupplementtheringbondsautomaticallyidentifiedbyDOCK.
Suchatechniquewouldbeusedtopreservetheconformationofpartofthemoleculeandisolateitfromtheconformationsearch.
Non-rotatablebondsareidentifiedintheTriposMOL2formatfilecontainingthemolecule.
ThebondsaredesignatedasmembersofaSTATICBONDSETnamedRIGID(seeTriposMOL2Format).
CreationoftheRIGIDsetcanbedonewithinChimera.
WiththemoleculeofinterestloadedintoChimera,selecttheportionoftheligandyouwouldliketoremainrigid.
ThenselectonFile>SaveMOL2.
Makesurethe"Writecurrentselectionto@SETSsectionoffile"ischeckedandsavethefile.
Alternatively,theRIGIDsetcanbeenteredintotheMOL2filebyhand.
Todothis,gototheendoftheMOL2file.
Ifnosetscurrentlyexist,thenaddaSETidentifieronanewline.
Itshouldcontainthetext"@SET".
Onanewlineaddthetext"RIGIDSTATICBONDS****Comment".
Onthenextlineenterthenumberofbondsthatwillbeincludedintheset,followedbythenumericalidentifierofeachbondintheset.
RETURNTOTABLEOFCONTENTS2.
7.
4.
IdentificationofFlexibleLayersAnanchorsegmentisselectedfromtherigidsegmentsinanautomaticfashion(seeseeManualSpecificationofNon-rotatableBondstooverridethisbehavior).
Themoleculeisdividedintosegmentsthatoverlapateachrotatablebond.
Thesegmentwiththelargestnumberofheavyatomsisselectedastheanchor.
Allsegmentswithmoreheavyatomsthenmin_anchor_sizearetriedseparatelyasanchors.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm20of659/18/20072:30PMIdentificationofOverlappingSegmentsWhenananchorhasbeenselected,thenthemoleculeisredividedintonon-overlappingsegments,whicharethenarrangedconcentricallyabouttheanchorsegment.
Segmentsarereattachedtotheanchoraccordingtotheinnermostlayerfirst--andwithinalayer--thelargestsegmentfirst.
LayeredNon-OverlappingSegmentsTheanchorisprocessedseparately(eitheroriented,scored,and/orminimized).
Theremainingsegmentsaresubsequentlyre-attachedduringtheconformationsearch.
Theinteractionenergybetweenthereceptorandtheligandcanbeoptimizedwithasimplexminimizer(seeMinimization).
RETURNTOTABLEOFCONTENTS2.
7.
5.
PruningtheConformationSearchTreeTherearenowtwoavailablemethodsforpruningavailable.
Inthefirst,thepruningattemptstoretainthebest,mostdiverseconfigurationsusingatop-firstpruningmethod,whichproceedsasfollows.
Theconfigurationsarerankedaccordingtoscore.
Thetop-rankedconfigurationissetasideandusedasareferenceconfigurationforthefirstroundofpruning.
Allremainingconfigurationsareconsideredcandidatesforremoval.
Aroot-mean-squareddistance(RMSD)betweeneachcandidateandthereferenceconfigurationiscomputed.
EachcandidateisthenevaluatedforremovalbasedonitsrankandRMSDusingtheinequalityshowninEquation2.
Ifthefactorisgreaterthannumber_confs_for_next_growth,asappropriate,thecandidateisremoved.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm21of659/18/20072:30PMBasedonthisfactor,aconfigurationwithrank2and0.
2AngstromsRMSDiscomparabletoaconfigurationwithrank20and2.
0AngstromsRMSD.
Thenextbestscoringconfigurationwhichsurvivesthefirstpassofremovalisthensetasideandusedasareferenceconfigurationforthesecondroundofpruning,andsoon.
Thepruningmethodbiasesitssearchtimetowardsmoleculeswhichsampleamorediversesetofbindingmodes.
Asthevalueofnum_anchors_orients_for_growthandnumber_confs_for_next_growthisincreased,theanchor-firstmethodapproachesanexhaustivesearch.
Inthesecondmethod,thegoalistobiasthesamplingtowardconformationsthatareclosetothecorrectbindingmode(asoptimizedusingatestsetofexperimentallysolvedstructures).
Muchasthemethodabove,thealgorithmranksthegeneratedposesandconformations.
Then,allposesthatviolateauser-definedscorecutoffareremoved.
Tofacilitatethespeedofthecalculation,theremaininglistisadditionallyparedbacktoauser-definedlength.
Inthistechnique,thesamplingisdriventowardsmoleculesthatsampleclosertotheexperimentallydeterminedbindingsite,butresultsinasignificantlylessdiversesetoffinalposes.
RETURNTOTABLEOFCONTENTS2.
7.
6.
InternalEnergyCalculationDuringthegrowthphaseofthecalculation,aninternalenergyscoringfunctioncanbeused.
ThisfunctioncomputestheLennard-JonesandCoulombicenergybetweenallligandatompairs,excludingall1-2,1-3,and1-4pairs.
Itreducestheoccurrenceofinternalclashesduringthetorsionaloptimization.
Thisenergyisnotincludedinthefinalreportedscore.
RETURNTOTABLEOFCONTENTS2.
7.
7.
TimeRequirementsThetimedemandgrowslinearlywiththenum_anchors_orients_for_growth,thenumber_confs_for_next_growth,thenumberofflexiblebondsandthenumberoftorsionpositionsperbond,aswellasthenumberofanchorsegmentsexploredforagivenmolecule.
UsingthenotationintheWorkflowforAnchor-and-GrowAlgorithm,thetimedemandcanbeexpressedaswheretheadditionaltermsare:NAisthenumberofanchorsegmentstriedpermolecule.
NBisthenumberofrotatablebondspermolecule.
RETURNTOTABLEOFCONTENTSNOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm22of659/18/20072:30PMInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
FlexibleLigandParametersflexible_ligand[yes](yes,no):#Flagtoperformligandconformationalsearchingmin_anchor_size[40](int):#Theminimumnumberofheavyatomsforananchorsegmentpruning_use_clustering[yes](yes,no):#Flagtoenableclusteringduringpruning(duplicatespreviousbehavior)(ifpruning_use_clustering=yes)pruning_max_orients[100](int):#Thepruningvaluecutoffforanchororientationspromotedtotheconformational#search(previouslynum_anchor_orients_for_growth)pruning_clustering_cutoff[100](int):#Themaximumnumberofconformationscarriedforwardintheanchor&growsearch#(previousnum_confs_for_next_growth)(ifpruning_use_clustering=no)pruning_max_orients[100](int):#Maximumnumberofanchororientationspromotedtotheconformational#searchpruning_orient_score_cutoff[25.
0](float):#Maximumscoreforanchorafterminimizationpruning_max_conformers[75](int):#Maximumnumberofanchororientationspromotedtothenextlayerofgrowthpruning_conformer_score_cutoff[25.
0](float):#Maximumscoreforconformationafterminimizationuse_internal_energy[yes](yes,no):#Flagtoaddaninternalenergytermtothescoreduringtheconformationalsearchinternal_energy_att_exp[6](int):#VDWattractiveexponentinternal_energy_rep_exp[12](int):#VDWrepulsiveexponentinternal_energy_dielectric[4.
0](float):#Dielectricusedforelectrostaticcalculationuse_clash_overlap[no](yes,no):#Flagtocheckforoverlappingatomvolumesduringanchorandgrowclash_overlap[0.
5](float):#PercentofoverlapallowedbeforeaclashisdeclaredRETURNTOTABLEOFCONTENTS2.
8.
ScoringDOCKusesseveraltypesofscoringfunctionstodiscriminateamongorientationsandmolecules.
Scoringisrequestedusingthescore_moleculesparameter.
Thescoringfunctionsareimplementedwithahierarchicalstrategy.
AmasterscoreclassmanagesallscoringfunctionsthatDOCKuses.
AnyoftheDOCKscoringfunctionscanbeselectedastheprimaryand/orthesecondaryscoringfunction.
Theprimaryscoringfunctionisusedduringrigidorienting,anchor-and-growsteps,andminimization,whichtypicallymakemanycallstothescoringfunction.
Thesecondaryscoringfunctionisusedinthefinalminimization,scoring,andrankingofthemolecules.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm23of659/18/20072:30PMRETURNTOTABLEOFCONTENTS2.
8.
1.
BumpFilterOrientationsandgrowstepsmaybefilteredpriortoscoringtodiscardthoseinwhichthemoleculesignificantlyoverlapsreceptoratoms.
Thisfeatureisenabledwiththebump_filterflag.
Atthetimeofconstructionofthebumpfilter,theamountofatomVDWoverlapisdefinedwiththebump_overlapparameter(seeGrid).
Atthetimeofbumpevaluationthenumberofallowedbumpsisdefinedwiththemax_bump_anchorandmax_bump_growthparameter.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
BumpFilterParametersbump_filter[yes](yes,no):#Flagtoperformbumpfilteringbump_grid_prefix[grid](string):#Theprefixtothegridfilecontainingthedesiredbumpgridmax_bumps_anchor[12](int):#Themaximumallowednumberofbumpsforamoleculetopass#thefiltermax_bumps_growth[12](int):#Themaximumallowednumberofbumpsforamoleculetopass#thefilterRETURNTOTABLEOFCONTENTS2.
8.
2.
ContactScoreThecontactscoreisasimplesummationofthenumberofheavyatomcontactsbetweentheligandandreceptor.
Atthetimeofconstructionofthecontactscoringgrid,thedistancethresholddefiningacontactissetwiththecontact_cutoff_distance(seeGrid).
AtomVDWoverlapsarepenalizedbycheckingthebumpfiltergrid,orwiththecontact_clash_overlapparameterfortheintramolecularscore.
Theamountofpenaltyisspecifiedwiththecontact_clash_penaltyparameter.
Thecontactscoreprovidesasimpleassessmentofshapecomplementarity.
Itcanbeusefulforevaluatingprimarilynon-polarinteractions.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm24of659/18/20072:30PMasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
ContactScoreParameterscontact_score_primary[no](yes,no):#Flagtoperformcontactscoringastheprimaryscoringfunctioncontact_score_secondary[no](yes,no):#Flagtoperformcontactscoringasthesecondaryscoringfunctioncontact_score_cutoff_distance[4.
5](float):#Thedistancethresholddefiningacontactcontact_score_clash_overlap[0.
75](float):#Contactdefinitionforusewithintramolecularscoringcontact_score_clash_penalty[50](float):#Thepenaltyforeachcontactoverlapmadecontact_score_grid_prefix[grid](string):#Theprefixtothegridfilescontainingthedesiredcontact#gridRETURNTOTABLEOFCONTENTS2.
8.
3.
Grid-BasedScoreThegrid-basedscoreisbasedonthenon-bondedtermsofthemolecularmechanicforcefield(seeGridformorebackground).
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
GridScoreParametersgrid_score_primary[yes](yes,no):#Flagtoperformgrid-basedenergyscoringastheprimaryscoring#functiongrid_score_secondary[yes](yes,no):#Flagtoperformgrid-basedenergyscoringasthesecondary#scoringfunctiongrid_score_rep_rad_scale[1](float):#Scalarmultiplieroftheradiifortherepulsiveportionofthe#VDWenergycomponentONLYgrid_score_vdw_scale[1](float):#ScalarmultiplieroftheVDWenergycomponent(ifgrid_score_vdw_scale=0)grid_score_turn_off_vdw[yes](yes,no):#Flagtoturnofvdwportionofscoringfunctiongrid_score_es_scale[1](float):#Theprefixtothegridfilescontainingthedesiredenergy#gridDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm25of659/18/20072:30PM(ifgrid_score_es_scale=0)grid_score_turn_off_es[yes](yes,no):#Flagtoturnofesportionofscoringfunctiongrid_score_grid_prefix[grid](string):#TheprefixtothegridfilescontainingthedesirednrggridRETURNTOTABLEOFCONTENTS2.
8.
4.
DOCK3.
5ScoreDOCK3.
5scoreisavariantofGrid-basedscoring(seeGrid).
DOCK3.
5scorefunctioncalculatesliganddesolvationinadditiontostericandelectrostaticinteractionsbetweentheligandandreceptor.
Theelectrostaticinteractionsbetweentheligandandtheproteiniscalculatedfromaelectrostaticpotential(ESP)map.
TheESPmapshouldbecalculatedusingfinitedifferencePoisson-Boltzmannequation(PBE)asimplementedintheprogramDelPhi.
Weprovidescriptsforthecalculation,howeverDelPhiisnotdistributedbyus.
IntheDOCKscoringhierarchyDOCK3.
5ScorefollowsGridScoreandcanbeusedbothastheprimaryandthesecondaryscoringfunction.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
DOCK3.
5ScoreParametersdock3.
5_score_primary[no](yes,no):#Flagtoperformdock3.
5scoringastheprimaryscoringfunctiondock3.
5_score_secondary[no]#Flagtoperformdock3.
5scoringasthesecondaryscoring#functiondock3.
5_vdw_score[yes](yes,no):#Calculatestericinteractionfromdock3.
5scoredock3.
5_grd_prefix[chem52](string):#Defaultprefixforfilescontainingdock3.
5gridsdock3.
5_electrostatic_score[yes](yes,no):#CalculateelectrostaticinteractionfromESPgridcalculatedusingDelPhidock3.
5_ligand_internal_energy[no](yes,no):#Flagtoaddligandinternalenergytothescoringfunctiondock3.
5_ligand_desolvation_score[volume](volume,total,no):#Calculatetotalorvolumebasedliganddesolvationfromsolvation#gridsdock3.
5_solvent_occlusion_file[solvmap](string):#Occludedsolventgridofthereceptordock3.
5_redistribute_positive_desolvation[no](yes,no):DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm26of659/18/20072:30PM#positivepartialatomicdesolvationpenaltiesaredistributeddock3.
5_write_atomic_energy_contrib[no](yes,no):#writecontributionfromeachatomtototalscoredock3.
5_score_vdw_scale[1.
0](float):#ScalarmultiplierofVDWenergycomponentdock3.
5_score_es_scale[1.
0](float):#ScalarmultiplierofelectrostaticenergycomponentRETURNTOTABLEOFCONTENTS2.
8.
5.
ContinuousScoreContinuousscoringmaybeusedtoevaluatealigand:receptorcomplexwithouttheinvestmentofagridcalculation,ortoperformamoredetailedcalculationwithoutthenumericalapproximationofthegrid.
Whencontinuousscoringisrequested,thenscoreparametersnormallysuppliedtogrid,mustalsobesuppliedtoDOCK.
Itislefttotheusertomakesureconsistentvaluesaresuppliedtobothprograms.
ThedistancedependenceoftheLennard-Jonesfunctionissetwiththecont_score_att_expandcont_score_rep_expparameters.
Typicallya6-12potentialisused,butitcanbesoftenedupbyusinga6-8or6-9potential.
Regardlessoftheexponentvaluesselected,thesameradiiandwell-depthsareused.
ThedistancedependenceoftheCoulombicfunctionissetwiththedistance_dielectricparameter.
Thedielectricconstantisadjustedwiththecont_score_dielectricparameter.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
ContinuousScoreParameterscontinuous_score_primary[no](yes,no):#Flagtoperformcontinuousnon-gridbasedscoringastheprimary#scoringfunctioncontinuous_score_secondary[no](yes,no):#Flagtoperformcontinuousnon-gridbasedscoringasthe#secondaryscoringfunctioncont_score_rec_filename[receptor.
mol2](string):#Filethatcontainsreceptorcoordinatescont_score_att_exp[6](int):#VDWLennard-Jonespotentialattractiveexponentcont_score_rep_ex[12](int):#VDWLennard-Jonespotentialrepulsiveexponentcont_score_dielectric[4.
0](float):#DielectricconstantforelectrostatictermDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm27of659/18/20072:30PMcont_score_vdw_scale[1](float):#Scalarmultiplierofvdwenergycomponent(ifcont_score_vdw_scale=0)cont_score_turn_off_vdw[yes](yes,no):#Flagtoturnofvdwportionofscoringfunctioncont_score_es_scale[1](float):#Scalarmultiplierofelectrostaticenergycomponent(ifcont_score_es_scale=0)cont_score_turn_off_es[yes](yes,no):#FlagtoturnofesportionofscoringfunctionRETURNTOTABLEOFCONTENTS2.
8.
6.
ZouGB/SAScoreTheZouGB/SAscoringfunctionisafastalgorithm,thepairwisefreeenergymodel,forligandbindingaffinitycalculations.
Specifically,apairwisedescreeningapproximation(Hawkins,etal.
Chem.
Phys.
Lett.
1995)isusedincalculationsoftheelectrostaticenergycontribution.
Thealgorithmalsoincludesaproceduretoaccountforthelowdielectricregionthatmightformbetweentheligandandthereceptorduringdockingprocesses.
Ithasbeentestedtoobtainsimilarresultscomparedwiththegrid-basedfreeenergymodelbutwithmuchlesscomputationefforts.
Formoreinformationonthescoringfunctionandspecificsoftheimplementation,seeLiu,etalJ.
Phys.
Chem.
B.
2004.
ZouGB/SAScoreParametersgbsa_zou_score_primary[no](yes,no):#FlagtoperformZouGB/SAscoringastheprimaryscoring#functiongbsa_zou_score_secondary[no](yes,no):#FlagtoperformZouGB/SAscoringasthesecondaryscoring#functiongbsa_zou_gb_grid_prefix[gb_grid](string):#ThepathtothepairwiseGBgridsgbsa_zou_sa_grid_prefix[sa_grid](string):#ThepathtotheSAgridsgbsa_zou_vdw_grid_prefix[grid](string):#Thepathtothenrggrids,usedforthevdwportionoftheGB/SAcalculationgbsa_zou_screen_file[screen.
in](string):#GBparameterfileforelectrostaticscreening.
Itslocatedintheparametersdirbydefaultgbsa_zou_solvent_dielectric[78.
300003](float):#ThevalueforthesolventdielectricRETURNTOTABLEOFCONTENTS2.
8.
7.
HawkinsGB/SAScoreTheHawkinsGB/SAscoreisanimplementationoftheMolecularMechanicsGeneralizedBornSurfaceArea(MM-GBSA)methodoriginallydescribedby(Srinivasan,etal.
J.
Am.
Chem.
Soc.
1998)andDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm28of659/18/20072:30PMreviewedby(Kollman,etal.
Acc.
Chem.
Res.
2000).
ThisparticularimplementationofMM-GBSAusesthepairwiseGBsolvationmodelreportedbyHawkins,CramerandTruhlar(Hawkins,etal.
Chem.
Phys.
Lett.
1995,Hawkins,etal.
J.
Phys.
Chem.
1996)withparametersdescribedbyTsuiandCase(Tsui,etal.
Biopolymers2001).
SolventAccessibleSurfaceAreas(SA)arecomputedusingaC++implementationoftheAmber8"icosahedra"algorithm.
ThetotalinteractionbetweentheligandandreceptorarerepresentedbyunscaledCoulombicandLennardjonesenergyterms(MM)plusthechange(delta)insolvation(GBSA)wheredeltaGBSA=GBSAcomplex-(GBSAreceptor+GBSAligand).
ForanygivenspeciesGBSA=Gpolar(GBenergy)+Gnonpolar(SA*0.
00542+0.
92).
Notethatifinnerandouterdielectricconstantsaresetto1(gas-phase)and80(water-phase),thenGBSAtermsareformallyequivalenttofreeenergiesofhydrationthatcanbedirectlycomparedwithexperimentaldataandusefulforevaluatingtheaccuracyofdifferentpartialchargemodels(Rizzoetal.
J.
Chem.
Theory.
Comput.
2006).
TheHawkinsGB/SAscorewasintendedtobeusedfor"single-point"calculationsandthecurrentimplementationisquiteslowifenergyminimizationisperformedatthesametime.
However,anenergyminimizationishighlyrecommendedpriortoGBSAsingle-pointcalculationsgiventhatscorescanbeverysensitivetoreceptor-ligandgeometry.
Useofthe-vflagwillyieldseparateGBSAtermsforeachspecies(complex,receptor,andligand)andalsoincluderawicosahedraSAvaluesinunitsofangstromssquared.
Thisscoringmethodrequiresthatthevdw_AMBER_parm99.
defnfilebespecifiedwhichcontainsGBradiiandscaleparametersforeachatomtype.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
HawkinsGB/SAScoreParametersgbsa_hawkins_score_primary[no](yes,no):#FlagtoperformHawkinsGB/SAscoringastheprimaryscoring#functiongbsa_hawkins_score_secondary[no](yes,no):#FlagtoperformHawkinsGB/SAscoringasthesecondaryscoring#functiongbsa_hawkins_score_rec_filename[receptor.
mol2](string):#Filethatcontainsreceptorcoordinatesgbsa_hawkins_score_solvent_dielectric[78.
5](float):#Dielectricconstantforsolventgbsa_hawkins_score_salt_conc(M)[0.
0](float):#SaltconcentrationforsolventatMolarconcentrationgbsa_hawkins_score_gb_offset[0.
09](float):DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm29of659/18/20072:30PM#GBradiusoffsetgbsa_hawkins_score_cont_vdw_and_es[yes](yes,no):#Flagtodeterminewhethervdwandesvalueswillbe#calculatedcontinuouslyorfromagrid(ifgbsa_hawkins_score_cont_vdw_and_es=yes)gbsa_hawkins_score_vdw_att_exp[6](int):#VDWLennard-Jonespotentialattractiveexponentgbsa_hawkins_score_vdw_att_exp[12](int):#VDWLennard-Jonespotentialrepulsiveexponent(ifgbsa_hawkins_score_cont_vdw_and_es=no)gbsa_hawkins_score_vdw_att_exp[6](int):#VDWLennard-Jonespotentialattractiveexponentgbsa_hawkins_score_vdw_att_exp[12](int):#VDWLennard-JonespotentialrepulsiveexponentRETURNTOTABLEOFCONTENTS2.
8.
8.
PB/SAScoreThePB/SAscoringfunctionisanimplementationoftheZAPtoolkitfromOpenEye.
InordertoaccessthePB/SAfunction,youmusthavetheZAPtoolkitinstalledandavalidZAPlicense.
Formoreinformationonobtainingthetoolkit,licensing,andotherOpenEyeproducts,gototheOpenEyewebpageatwww.
eyesopen.
comFromtheOpenEyeDocumentation:"ASmoothPermittivityFunctionforPoisson-BoltzmannSolvationMethods",J.
AndrewGrant,BarryT.
PickupandAnthonyNicholls,J.
Comp.
Chem,Vol22,No.
6,pgs608-640,April2001.
ZAPis,atitsheart,aPoisson-Boltzmann(PB)solver.
ThePoissonequationdescribeshowelectrostaticfieldschangeinamediumofvaryingdielectric,suchasanorganicmoleculeinwater.
TheBoltzmannbitaddsintheeffectofmobilecharge,e.
g.
salt.
PBisaneffectivewaytosimulatetheeffectsofwaterinbiologicalsystems.
Itreliesonachargedescriptionofamolecule,thedesignationoflow(molecular)andhigh(solvent)dielectricregionsandadescriptionofanion-accessiblevolumeandproducesagridofelectrostaticpotentials.
Fromthis,transferenergiesbetweendifferentsolvents,bindingenergies,pkashifts,pI's,solventforces,electrostaticdescriptors,solventdipolemoments,surfacepotentialsanddielectricfocusingcanallbecalculated.
Aselectrostaticsisoneofthetwoprincipalcomponentsofmolecularinteraction(theother,ofcourse,beingshape),ZAPisOpenEye'sattempttogetitright.
ZAPiswritteninANSICandfollowsastyleofobject-orientedprogrammingpopularizedinthechemicalinformationworldbyDaylight.
Itencapsulatesstructuresandmethodsbytheuseofopaquepointers,orhandles.
Theseareintegersconvertedtorealpointersintheinterioroftheobjectsystem,hiddenfromtheuser.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm30of659/18/20072:30PMZAPisavailabletomostacademicandgovernmentinstitutionsfreeofcharge.
ItcomesintheformofalinkablelibraryandasetofprepackagedbinariescompiledforSGI,LinuxandCygwin(NT).
Commercialuserequiresalicense,availableataveryreasonablecostfromthenicefolksatOpenEye.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
PB/SAScoreParameterspbsa_score_primary[yes](yes,no):#Flagtoperformpbsaenergyscoringastheprimaryscoring#functionpbsa_score_secondary[yes](yes,no):#Flagtoperformpbsaenergyscoringasthesecondary#scoringfunctionpbsa_receptor_filename[receptor.
mol2](string):#Nameofreceptorfile.
pbsa_interior_dielectric[2.
0](float):#Valueforthedielectricinsidetheproteinpbsa_exterior_dielectric[78.
5](float):#Valueforthedielectricofthesolvent(outsidetheprotein)pbsa_vdw_grid_prefix[grid](string):#TheprefixtothegridfilescontainingtheVDWvaluesRETURNTOTABLEOFCONTENTS2.
8.
9.
AMBERScoreTheAMBERscoreprovidesasuiteoffunctionalityincluding:AMBERmolecularmechanics,implicitsolvation,andmoleculardynamicssimulation,receptorflexibility,andconjugategradientminimization.
Themaindisadvantagesaremorecomplicatedinputpreparationandincreasedcomputationalexpense.
AMBERscoreimplementsmolecularmechanicsimplicitsolventsimulationswiththetraditionalall-atomAMBERforcefield(Pearlman,etal.
Comp.
Phys.
Commun.
1995)forproteinatomsandthegeneralAMBERforcefield(GAFF,Wang,etal.
J.
Comp.
Chem.
2004)forligandatoms.
TheinteractionbetweentheligandandthereceptorisrepresentedbyelectrostaticandvanderWaalsenergyterms,andthesolvationenergyiscalculatedusingaGeneralizedBorn(GB)solvationmodel.
TheuserhastheoptiontochooseoneofthefollowingGBmodels:(i)Hawkins,CramerandTruhlarpairwiseGBmodelwithparametersdescribedbyTsuiandCase(gb=1)(Tsui,etal.
Biopolymers2001),(ii)Onufriev,BashfordandCasemodel,GB(OBC)(gb=2)(Onufriev,etal.
Proteins2004),and(iii)amodifiedGB(OBC)(gb=5)(Onufriev,etal.
Proteins2004).
ThesurfaceareatermisDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm31of659/18/20072:30PMderivedusingafastLCPOalgorithm(Weiser,etal.
J.
CompChem1999).
TheAMBERscoreiscalculatedas:E(Complex)-[E(Receptor)+E(Ligand)],whereE(Complex),E(Receptor),andE(Ligand)representtheenergiesofthecomplex,receptor,andligand,respectively.
Thecalculationofeachofthesethreeenergiesusesthesameprotocol:minimizationwithaconjugategradientmethodisfollowedbyMDsimulation(Langevinmoleculardynamicsatconstanttemperature),anotherminimization,andafinalenergyevaluation.
Theusercanspecifythenumberofpre-MD-minimizationcycles,thenumberofMDsimulationsteps,andthenumberofpost-MD-minimizationcyclesinthedockinputfile.
Duringthefinalenergyevaluation,asurfaceareatermisincluded.
Thereceptorenergyisdeterminedonce.
TheAMBERscoreenergyprotocolisperformedforeveryligandanditscorrespondingcomplex.
AMBERscoreenablesallorapartofthereceptortobeflexible,inordertoreproducetheso-called"induced-fit".
TheCartesiancoordinatesofatomsthatareflexiblecanbealteredduringtheAMBERscoreenergyprotocol.
TheCartesiancoordinatesofatomsthatarenotflexiblecannotbealteredduringtheAMBERscoreenergyprotocol.
Theflexiblepartsofthereceptor-ligandcomplexarespecifiedwithamovableregiondockinputfileparameter.
Themovableregionoptionsareligand,everything,nothing,distance,andNABatomexpression.
Fortheligandoption,onlytheligandisallowedtomoveduringminimizationandMDsimulation.
Fortheeverythingoption,alltheatomsinthereceptorandtheligandareallowedtomove.
NominimizationorMDsimulationoccursforthenothingoption.
ThisistheonlymovableregionoptionforwhichtheligandisnotflexibleduringtheAMBERscoreenergyprotocol.
Consequently,closecontactscanproduceverylargeenergiesbecausetheAMBERforcefieldcanbesensitivetothereceptor-ligandgeometry.
However,thenothingoptionisthefastesttypeofAMBERscoring.
Thedistancemovableregionoptionselectsresiduesthatareallowedtomovebyreceptor-liganddistance.
IfanyatominareceptorresidueiswithinthedockinputfileparameterdistancecutoffAngstromsoftheligandthenthewholeresidueisselected.
Theligandisrepresentedbytheactivesitespherelist,andthusthemovablereceptorresiduesarewelldefinedandindependentofanyparticularligandmolecule.
Theligandisalwaysmovable.
Theselectedresiduesareemittedwiththe-vverboseflagasaNABatomexpression.
TheNABatomexpressionmovableregionoptionisbasedontheprogramNucleicAcidBuilder(NAB).
EveryatominaNABmoleculehasauniquename.
Thisnameiscomposedofthestrandname,theresiduenumberandtheatomname.
ANABatomexpressionisacharacterstringthatcontainsoneormorepatternsthatmatchasetofatomnamesinamolecule.
Thedockinputfileparameterassociatedwiththisoptionspecifiesthesetofatomsinthereceptorthataremovable.
Allatomsoftheligandaremovable.
InDOCKastrandnameisinfactastrandsequencenumber,andinareceptor-ligandcomplex,theligandisalwayslastinthesequence.
Thus,areceptormoleculeDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm32of659/18/20072:30PMwithtwostrandshasstrandnamesof"1"and"2";inacorrespondingreceptor-ligandcomplextheligand(whichisalmostcertainlysinglestranded)hasstrandname"3".
NABatomexpressionscontainthreesubexpressionsseparatedbycolons.
Theyrepresentthestrand,residueandatompartsoftheatomexpression.
Notallthreepartsarerequired.
Anemptypartselectsallstrands,residuesoratomsdependingonwhichpartsareempty.
Eachsubexpressionconsistsofacommaseparatedlistofpatterns,orfortheresiduepart,patternsand/ornumberranges.
Severalatomexpressionsmaybeplacedinasinglecharacterstringbyseparatingthemwiththeverticalbar.
PatternsinatomexpressionsaresimilartoUnixshellexpressions.
Eachpatternisasequenceofoneormoresinglecharacterpatternsand/orstars.
Thestarmatcheszeroormoreoccurrencesofanysinglecharacter.
Eachpartofanatomexpressioniscomposedofacommaseparatedlistoflimitedregularexpressions,orinthecaseoftheresiduepart,limitedregularexpressionsand/orranges.
Arangeisanumberorapairofnumbersseparatedbyadash.
TheNABmanualcontainsmoreinformationonatomexpressions.
HerearesomeexamplesofNABatomexpressions::SER:#SelectallatomsinanyresiduenamedSER.
Allthreepartsarepresentbutboththestrandandatompartsareempty.
Theatomexpression:SERselectsthesamesetofatoms.
::C,CA,N,O#SelectallatomswithnamesC,CA,NorOinallresiduesinallstrands(typicallythepeptidebackbone).
1:1-10,13:CA,C,N#SelectallatomsnamedCA,C,Ninresidues1-10and13instrand1.
::C*[^1]#The[^1]isanexampleofanegatedcharacterclass.
Itmatchesanycharacterinthelastpositionexcept1.
Inthiscase,itwillmatchalltheatomsstartingwithC,suchasCA,CB,CG2,butnotthoseendingwith1,suchasCD1,CE1.
2::|1:50,100:O*,N*#Selectallatomsinstrand2.
SelectallatomswhosenamestartswithOandNinresidue50,100instrand1.
Notethattheverticalbarseparatesthetwostrands4::|2::|1::#Selectstrand4,2and1.
::or:#Selectallatomsinthemolecule.
Alltheinputfiles,suchastheprmtop,frcmod,amber.
pdb,etc.
shouldbegeneratedpriortorunningtheAMBERscore.
Aperlscript,prepare_amber.
pl,hasbeenprovidedforthispurpose.
Theusageofprepare_amber.
plisprepare_amber.
plligand_mol2_filereceptor_PDB_fileForexample,iflig.
mol2isligand_mol2_file,andrec.
pdbisreceptor_PDB_file,thenuse:prepare_amber.
pllig.
mol2rec.
pdbThescript,prepare_amber.
pl,alsohastheabilitytoreadinamol2fileDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm33of659/18/20072:30PMcontainingmultipleligands(usuallytheoutputfromapreviousDOCKrun),andgenerateAMBERscorereadableinputfiles.
prepare_amber.
plcallsotherscriptsandprograms,suchasantechambertocalculatetheAM1-BCCchargesfortheligands,andtleaptoassigntheparm94parametersetforproteinatomsandtheGAFFparametersetforligandatoms.
Seethetutorialsforinformationonhowtousethescripttogeneratetheinputfiles.
WithknowledgeofandexperienceusingAMBERonecouldcreatetheinputfilesmanually;seetheamberizesciptsforthegorydetails.
Notethattheligand_atom_file,whichhastheextension".
amber_score.
mol2",musthaveaTRIPOSAMBER_SCORE_IDsection.
TheAMBERscoreoutputintheDOCKoutputcontainsenergytermsforeachspecies(complex,receptor,andligand)suchthatthesumofthetermsisequaltothescore.
UseoftheDOCK-vverboseflagwillproducedetailedenergybreakdowns;theformatsanddefinitionsofthisinformationarediscussedinthetheNABmanual:NucleicAcidBuilder(NAB).
TheverboseoutputisbestcapturedviaUNIXshellfileredirectionasopposedtotheDOCK-oflag.
TheAMBERscoreoutputintheligand_outfile_prefix_scored.
mol2filecontainstheligandcoordinatesextractedfromthefinalstructureofthecomplex(i.
e.
,thestructureaftertheAMBERscoreenergyprotocolisperformed).
Theligandchargesarefromtheligandprmtopfile.
TheligandatomtypesarethenormalonesfromDOCKandarenottheGAFFatomtypesusedbyAMBERscore.
TheAMBERscoreusesthefollowingmethodforemittingallthefinalstructuresintheirentirety.
TheAMBERscorewillcreateafilewiththeextension".
final_pose.
amber.
pdb"foreveryspecies(receptor,ligands,andcomplexes)thatcontainsanymovableregion(regardlessofwhetherthatregionactuallyexistsoractuallydoesmove).
Thus,forthedistance,everything,andNABatomexpressionoptionsofthemovableregion,afileforthereceptor(amber_score_receptor_file_prefix.
final_pose.
amber.
pdb)andtwoforeachligand,complexpair(AMBER_SCORE_ID.
final_pose.
amber.
pdb,amber_score_receptor_file_prefix.
AMBER_SCORE_ID.
final_pose.
amber.
pdb)willbecreated;forthenothingoptionofthemovableregion,nofileswillbecreated.
Inaddition,ifthe-vverboseflagispresentthentheAMBERscorewillcreateanAMBERrestartfilewiththeextension".
final_pose.
amber.
restart"foreveryspecies(receptor,ligands,andcomplexes)thatcontainsanymovableregion(regardlessofwhetherthatregionactuallyexistsoractuallydoesmove).
HereissomegeneraladviceontheAMBERscore.
Sinceitisslowerandmorecomplicatedthantheotherscoringfunctions,oneshouldproceedcarefullywhenusingtheAMBERscoreasthesoleprimaryscore.
Themostobvioususeistorescore,withthedefaultamber_scoreinputparameters,theligandsthathavebeenalreadyscoredusingoneofthefasterscoringfunctions.
Ingeneral,theinputpreparationforAMBERscoreismoreinvolvedthanfortheotherscores.
Effectively,oneneedstogenerateinputfilesforAMBER.
Inparticular,examinetheamberize*.
outand*.
logfilesforwarningsanderrors.
ExperienceusingAMBERwillhelpinunderstandingandjudgingtheimpactofthemessagesinthesefiles.
CorrectingproblemsDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm34of659/18/20072:30PMmayinvolvesubstantialeffort.
SeetheDOCKFansmailinglistforspecificexamples.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
AMBERScoreParametersamber_score_primary[no](yes,no):#Flagtoperformamberscoringastheprimaryscoringfunction.
amber_score_secondary[no](yes,no):#Flagtoperformamberscoringasthesecondaryscoringfunction.
Thisistemporarilydeprecated,andusinginputparameteramber_score_secondarycausesprogramtermination.
TherecommendedprotocolistoperformtwoDOCKrunswiththesecondrunspecifyingamber_scoreastheprimary_score.
amber_score_receptor_file_prefix[rec](string):#PrefixoftheReceptor.
Usetheprefixthatwasusedintheprepare_amber.
plinputfilepreparationstep.
amber_score_movable_region[ligand](distance,everything,ligand,nab_atom_expression,nothing):#Theregionthatwillbeflexibleduringthescoringprotocol.
amber_score_movable_distance_cutoff[3.
0](float):#AllreceptorresidueswithinthiscutoffinAngstromsoftheligandwillbemovable.
Thisisactiveonlyforamber_score_movable_region=distance.
receptor_site_file[receptor.
sph](string):#Thefilecontainingthereceptorspheresthatdefinetheactivesite.
Thisisnotspecifictoamber_score.
Thisisactiveforamber_score_movable_region=distance.
amber_score_movable_atom_expression[::](string):#NABatomexpressiondefiningthemovablereceptorregion.
Thisisactiveonlyforamber_score_movable_region=nab_atom_expression.
amber_score_before_md_minimization_cycles[100](int):#NumberofconjugategradientminimizationcyclestobeperformedbeforeMD.
amber_score_md_steps[3000](int):#NumberofMolecularDynamics(MD)stepstobeperformed.
amber_score_after_md_minimization_cycles[100](int):#NumberofconjugategradientminimizationcyclestobeperformedafterMD.
amber_score_gb_model[5](int):#GBmodeltobeused.
amber_score_nonbonded_cutoff[18.
0](float):#Non-bondedcutoffinAngstromsfortheenergyDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm35of659/18/20072:30PMcalculation.
amber_score_temperature[300.
0](float):#TemperatureatwhichMDshouldbeperformed.
RETURNTOTABLEOFCONTENTS2.
9.
MinimizationScoreoptimizationallowstheconformationandorientationofamoleculetobeadjustedtoimprovethescore.
Althoughthecalculationisexpensive,itmakestheconformationandorientationsearchmoreefficientbecauselesssamplingbecomesnecessary.
Optimizationisactivatedwiththeminimize_ligandparameter.
Theoptimizercurrentlyusesthesimplexalgorithm,whichdoesnotrequireevaluationofderivatives(Nelderetal,ComputerJournal,1964).
Itdoeshoweverdependonarandomnumbergeneratorwhichmakesitsensitivetotheinitialseedprovidedwithrandom_seedparameter.
Theamountofvarianceshouldbesmall,though.
Fordetailedcalculations,itisrecommendedthattheoptimizationberepeatedwithdifferentrandomnumberseedstocheckconvergence.
Theinitialstepsizeoftheminimizerisspecifiedwiththeinitial_translation,initial_rotation,andinitial_torsionparameters.
Thelengthofminimizationmaybecontrolledwiththemaximum_iterationsparameter.
Userscanchoosetominimizetherigidanchors,minimizeduringflexiblegrowth,andminimizethefinalconformation.
Theanchorminimizationisalwaysdonerigidly;also,ifnoflexiblegrowthisbeingdone,thisstepwillminimizetheentiremolecule.
Theminimizationduringtheflexiblegrowthisacomplete(torsions+rigid)minimization.
Whenthesimplexshrinksenoughsothatthehighestandlowestpointsarewithinthescoringtoleranceorifthenumberofrequestedminimizerstepsisreached,theminimizerterminates.
RETURNTOTABLEOFCONTENTSNOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
ScoreOptimizationParametersminimize_ligand[yes](yes,no):#Flagtoperformscoreoptimization(ifflexible_ligand=no)simplex_max_iterations[50](int):#Maximumnumberofminimizationcycles(ifflexible_ligand=yes)minimize_anchor[yes](yes,no):#Flagtoperformrigidoptimizationoftheanchorsimplex_anchor_max_iterations[500](int):#MaximumnumberofiterationspercycleperanchorDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm36of659/18/20072:30PMminimize_flexible_growth[yes](yes,no):#Flagtoperformcompleteoptimizationduringconformationalsearchsimplex_grow_max_iterations[500](int):#Maximumnumberofiterationspercyclepergrowthstepuse_advanced_simplex_parameters[no](yes,no):#Flagtouseasimplifiedsetofcommonminimizationparametersforeachofthe#minimizationstepslistedabove(seebelowforlistoftheseoptions)(ifminimize_ligand=yes)simplex_final_min[no](yes,no):#Flagtoperformonemorecycleofminimizationoneachfullygrownposesimplex_final_max_iterations[0](int):#Maximumnumberofiterationsforfinalcyclesimplex_final_min_rep_rad_scale[1](float):#Scalarmultiplieroftheradiifortherepulsiveportionofthe#VDWenergycomponentONLYsimplex_final_min_add_internal[no](yes,no):#Flagtoaddligandinternalenergytoprimaryscoringfunction(ifsecondary_score=yes)simplex_secondary_minimize_pose[yes](yes,no):#Flagtoperformanadditionalcycleofminimizationusingthesecondaryscoring#functionuse_advanced_secondary_simplex_parameters[no](yes,no):#Flagtouseasimplifiedsetofcommonminimizationparametersforeachofthe#minimizationstepslistedabove(seebelowforlistoftheseoptions)secondary_min_add_internal[no](yes,no):#Flagtoaddligandinternalenergytosecondaryscoringfunction(ifminimize=yes)simplex_random_seed[0](int):#SeedforrandomnumbergeneratorGenericMinimizerParametersifflexible_ligand=noORuse_advanced_simplex_parameters=no,XXX=simplex1.
ifuse_advanced_simplex_parameters=noANDminimize_anchor=yes,XXX=simplex_anchor2.
ifuse_advanced_simplex_parameters=noANDminimize_flexible_growth=yes,XXX=simplex_growth3.
ifuse_advanced_simplex_parameters=noANDsimplex_final_min=yes,XXX=simplex_final4.
ifsimplex_secondary_minimize_poseANDuse_advanced_secondary_simplex_parameters,XXX=simplex_secondary5.
XXX_max_cycles[1](int):#MaximumnumberofminimizationcyclesXXX_score_converge[0.
1](float):#ExitcycleatwhenenergyconvergesatcutoffXXX_cycle_converge[1.
0](float):#ExitminimizationwhencyclesconvergeatcutoffXXX_trans_step[1.
0](float):#InitialtranslationstepsizeDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm37of659/18/20072:30PMXXX_rot_step[0.
1](float):#InitialrotationstepsizeXXX_tors_step[10.
0](float):#InitialtorsionanglestepsizeRETURNTOTABLEOFCONTENTS2.
10.
ParameterFilesTheparameterfilescontainatomandbonddataneededduringDOCKcalculations.
Thedefinition(*.
defn)filescontainatomandbondlabelingdata.
Thetable(*.
tbl)filescontainadditionaldataforchemicalinteractionsandflexiblebondtorsionpositions.
Theymaybeeditedbytheuser.
Alltheparameterfilesdescribedbelowcanbefoundinthe"parameter"directoryintheDOCKdistribution.
RETURNTOTABLEOFCONTENTS2.
10.
1.
AtomDefinitionRulesThedefinitionfilesuseaconsistentatomlabelingconventionforwhichanatominvirtuallyanychemicalenvironmentcanbeidentified.
Thespecificationofadjacentatomsisnestedusingtheelementslistedbelow:Eachelementmustbeseparatedbyaspace.
Ifmorethanoneadjacentatomisspecified,thenALLmustbepresent(i.
e.
abooleanANDforruleswithinaline).
Ifalabelcanhavemultipledefinitionlines,thenanyONEofthemmustbesatisfiedforinclusion(i.
e.
abooleanORforrulesondifferentlines).
AtomDefinitionElementsElementFunctionatomtypeSpecifiespartialorcompleteatomtype.
Apartialspecificationismoregeneral(i.
e.
"C"versus"C.
3").
Anasterisk(*)specifiesANYatomtype.
()Specifiesatomsthatmustbebondedtoparentatom.
[]SpecifiesatomsthatmustNOTbebondedtoparentatom.
integerSpecifiesthenumberofanatomthatmustbebonded.
ExampleDefinitionsExampleExplanationDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm38of659/18/20072:30PMC.
2(2O.
co2)Acarboxylatecarbon.
.
3[3H]Anysp3hybridizedatomthatisnotattachedtothreehydrogens.
C.
[O.
][N.
[2O.
2][2C.
]]Anycarbonnotattachedtoanoxygenoranitrogen(unlessthenitrogenisanitroortertiarynitrogen).
RETURNTOTABLEOFCONTENTS2.
10.
2.
vdw.
defnThisfilecontainsatomlabelsanddefinitionsforvanderWaals(VDW)atomtyping.
Thefollowingdatatypesareassociatedwitheachatom:VDWradius,VDWwell-depth,flagforheavyatom,andvalence.
TheVDWradiusandVDWwell-depthvaluesareusedinmolecularmechanics-scoringfunctions(seeGrid).
Thevalenceisthevalueforthemaximumnumberofatomsthatcanbeattached.
ThedefinitionistheSybylatomtypesthatshouldbeassociatedwiththeatomname.
Alabelmayhavemultipledefinitions.
Inthevdw_AMBER_parm99.
defnfile,thereareadditionalparametersneededforusewiththeHawkinsGB/SAscoringfunction(seeHawkinsGB/SA).
Eachentryhasanadditionalgbraiiandgbscaleparameter.
WARNING:Thelastentryinthevdw.
defnfileMUSTbeDummy.
SampleEntriesnameCarbon_sp/sp2atom_modeleitherradius1.
850well_depth0.
120heavy_flag1valence4definitionCnameCarbon_All_sp3atom_modelallradius1.
800well_depth0.
060heavy_flag1valence4gbradii1.
70gbscale0.
72definitionC.
3DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm39of659/18/20072:30PMnameCarbon_United_CH3atom_modelunitedradius2.
000well_depth0.
150heavy_flag1valence4definitionC.
(3H)RETURNTOTABLEOFCONTENTS2.
10.
3.
chem.
defnThisfilecontainslabelsanddefinitionsforchemicallabeling.
Nothingoutsideofadditiontoalabelneedstobeassignedtoanatom.
Alabelmayhavemultipledefinitionlinesbutthenamesmustmatchtherulesinthechem_match.
tblfile.
SampleEntriesnamehydrophobicdefinitionC.
[O.
][N.
[2O.
2][2C.
definitionN.
pl3(3C.
)definitionCl(C.
)definitionBr(C.
)definitionI(C.
)definitionC.
3[*]namedonordefinitionN.
(H)definitionN.
4[*]nameacceptordefinitionO.
[H][N.
definitionO.
3(1*)[N.
]definitionO.
co2(C.
2(O.
co2))definitionN.
[H][N.
][O.
][3definitionO.
2[*]RETURNTOTABLEOFCONTENTS2.
10.
4.
chem_match.
tblThisfilecontainstheinteractionmatrixforwhichchemicallabelscanformaninteractioninmatching.
Thelabelsmustbeidenticaltolabelsinchem.
defn.
Thetableflagindicatesthebeginningoftheinteractiontable.
Compatiblelabelsareidentifiedwithaone,otherwiseazero.
SampleFileDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm40of659/18/20072:30PMlabelnulllabelhydrophobiclabeldonorlabelacceptorlabelpolartable111101100110111RETURNTOTABLEOFCONTENTS2.
10.
5.
flex.
defnThisfilecontainslabelsanddefinitionsforflexiblebondidentification.
Thedrive_idfieldcorrespondstoatorsiontypeintheflex_drive.
tblfile.
Theminimizefieldisaflagforwhetherthebondmaybeminimized.
Twodefinitionlinesmustbepresent.
Eachdefinitioncorrespondstoanatomateitherendofthebond.
SampleEntriesnamesp3-sp3drive_id3minimize1definition.
3[3H][3O.
co2]definition.
3[3H][3O.
co2]namesp3-sp2drive_id4minimize1definition.
3[3H][3O.
co2]definition.
2[2H][2O.
co2]namesp2-sp2drive_id2minimize0definition.
2[2H][2O.
co2]definition.
2[2H][2O.
co2]RETURNTOTABLEOFCONTENTS2.
10.
6.
flex_drive.
tblThisfilecontainstorsionpositionsassignedtoeachrotatablebondwhentheflexibledockingparameterisusedinDOCK.
Thedrive_idfieldcorrespondstoeachtorsiontypeintheflex.
defnfile.
Thepositionsfieldspecifiesthenumberoftorsionanglestosample.
Thetorsionsfieldspecifiestheanglesthataresampled.
SampleEntriesDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm41of659/18/20072:30PMdrive_id2positions2torsions0180drive_id3positions3torsions-6060180drive_id4positions4torsions-90090180RETURNTOTABLEOFCONTENTSNOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
AtomTypingParametersatom_model[all](all,united):#Choiceofallatomorunitedatommodelsvdw_defn_file[vdw.
defn](string):#FilecontainingVDWparametersforatomtypesflex_defn_file[flex.
defn](string):#Filecontainingconformationalsearchparameterschem_defn_file[chem.
defn](string):#Filecontainingchemicallabeldefinitionschem_match_tbl[chem_match.
tbl](string):#FilecontainingrulesforchemicalmatchingRETURNTOTABLEOFCONTENTS2.
11.
LigandFileOutputDOCKreportsseveralkindsofinformationasoutputwhichiseitherwrittentoscreenininteractivemodeorwrittentofileinbatchmode(seeInstallation).
Allinputparametersareechoedintotheoutput.
Ifaparameterisnotneededitisnotreportedintheoutput.
AtthecompletionofeachDOCKrun,thenumberofmoleculesthatwereprocessedandthetotaltimeofthecalculationisreported.
Theresultsofeachmoleculeareprintedintheoutfileaswell.
Dependingonthecombinationofuserparameters,eachmoleculeentrywillcontainthenumberofanchorsused(seeIdentificationofRigidSegments),thenumberoforientationsthatpassedpruning(seeOrientingtheLigand),thenumberoffullygrownconformationsthatpassedpruning(seePruningtheConformationSearchTree),andabreakdownoftheinteractionenergybetweentheligandandreceptor(seeScoring).
ExampleMoleculeSectionofOutputDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm42of659/18/20072:30PMMolecule:C1Anchors:1Orientations:1Conformations:1GridScore:-29.
223606vdw:-26.
868692es:-2.
254913Inadditiontotheinformationprintedtotheoutputfiles,thereareseveralstructuraloutputoptions.
Eachstructuralfilenameisformedusingtheligand_outfile_prefixparameter.
Inatypicalrun,thebestscoringposeofeachligandinthelibrarywillbewrittentoafilecalledoutputprefix_scored.
mol2.
Inaddition,thereareseveralmoreadvancedoutputoptions:(1)Userscanchoosetowriteoutorientations.
Thiswillcreateafilecalledoutputprefix_orients.
mol2.
Thiswillwriteoutthemoleculesaftertheyhavebeenrigidlyorientedandoptimized.
Ifanchor&growisbeingused,thisoptionwillwriteoutonlytheanchorfragment.
Allorientationsgeneratedwillbewrittenout,sobecarefulthattheoutputdoesnotgettoohuge.
(2)Userscanalsowriteoutconformersafterthefinallevelofoptimization.
Thiswillcreateafilecalledoutputprefix_conformers.
mol2.
Again,beawarethatthenumberofmoleculesintheoutputfilewillbeequaltothedatabasesize*the#ofanchorspermolecule*thenumberofconfomationsthatpassthefinalpruningstage*thenumberofconformerspercycle.
Thisfilecangrowquitelarge,soonlyuseitonsingleposesorsmalldatabases.
(NOTE:Ifclusteringisenabled,allconformationswillbewrittentotheoutputprefix_conformers.
mol2filewhiletheclusterheadswillbewrittentotheoutputprefix_scored.
mol2file.
Thisseeminglyredundantwritingistoensurethatnoportionoftheanalysisislostifafailureofsomekindoccurs).
(3)Userscanwritemoleculesrankedbyscore.
Thiswillcreateafilecalledoutputprefix_ranked.
mol2,whichwritesoutthetopNmoleculesfromthedatabase.
Thisoptiondisablesthescoredmoleculeoutputfilebydefault.
Ifsecondaryscoringisenabled,alloftheabovefileswillbegeneratedforbothprimaryandsecondaryscoring.
Thesecondaryscoringfileswillcontainboththeoriginalprimaryscoreaswellasthenewsecondaryscore.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
LigandFileOutputligand_outfile_prefix[output](string):#Theprefixthatalloutputfileswillusewrite_orientations[no](yes,no):DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm43of659/18/20072:30PM#Flagtowriteallanchororientations(ifsecondary_score=yes)num_primary_scored_conformers_rescored[1](int):#Thenumberofconformationsscoredandrankedusingtheprimaryscore#toberescoredbythesecondaryscore.
Conformationswrittento#ligand_outfile_prefix_primary_conformers.
mol2(ifnum_primary_scored_conformers_rescored>1):cluster_primary_conformations[yes](yes,no):#Flagtoenableclusteringoffullyminimizedconformationsfrom#primaryscore(ifcluster_primary_conformations=yes)cluster_rmsd_threshold[2.
0](float):#Thecutofftodeterminewhetherconformationsshouldbe#includedinaparticularclusternum_clusterheads_for_rescore[5](int):#Thenumberofclusterheadsscoredusingtheprimaryscore#toberescoredbythesecondaryscore.
Clusterheads#writtentoligand_outfile_prefix_primary_scored.
mol2num_secondary_scored_conformers_written[1](int):#Thenumberofconformationsscoredandrankedusingthe#secondaryscore.
Conformationswrittento#ligand_outfile_prefix_secondary_conformers.
mol2rank_primary_ligands[no](yes,no):#Flagtoenablerankingbyprimaryscoreoverallligands:#thesetofbestscoringposes,oneposeperligand,willbesortedby#primaryscoreintodescendingorder.
Thetopposeswillbewrittento#fileligand_outfile_prefix_primary_ranked.
mol2.
max_primary_ranked[500](int):#Themaximumnumberofligandstobestoredinthis_rankedfile.
rank_secondary_ligands[no](yes,no):#Flagtoenablerankingbysecondaryscoreoverallligands:#thesetofbestscoringposes,oneposeperligand,willbesortedby#secondaryscoreintodescendingorder.
Thetopposeswillbewrittento#fileligand_outfile_prefix_secondary_ranked.
mol2.
max_secondary_ranked[500](int):#Themaximumnumberofligandstobestoredinthis_rankedfile.
(ifsecondary_score=no)num_scored_conformers_written[1](int):DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm44of659/18/20072:30PM#Thenumberofconformationsscoredandrankedusingtheprimaryscore.
#Conformationswrittento#ligand_outfile_prefix_conformers.
mol2(ifnum_scored_conformers_written>1):cluster_conformations[yes](yes,no):#Flagtoenableclusteringoffullyminimizedconformationsfrom#primaryscore(ifcluster_conformations=yes)cluster_rmsd_threshold[2.
0](float):#Thecutofftodeterminewhetherconformationsshouldbe#includedinaparticularclusterrank_ligands[no](yes,no):#Flagtoenablerankingbyscoreoverallligands:#thesetofbestscoringposes,oneposeperligand,willbesortedby#scoreintodescendingorder.
Thetopposeswillbewrittento#fileligand_outfile_prefix_ranked.
mol2.
max_ranked_ligands[500](int):#Themaximumnumberofligandstobestoredinthis_rankedfile.
RETURNTOTABLEOFCONTENTS2.
12.
ParallelProcessingParallelprocessingisfullyintegratedintotheDOCKprogram.
ItissetuptohaveasingleMasternode,whiletheremainingnodesactasslaves.
TheMasternodeperformsfileprocessingandinput/output,whereastheslavesperformtheactualcalculations.
Ifthenumberofprocessors(np)is1thenthecodedefaultstothenon-MPIbehavior.
Asaresult,therewillbeaminimaldifferenceinperformancebetween1and2processors.
Improvedperformancewillonlybecomeevidentwithmorethan2processors.
ItshouldbeemphasizedthattheprimarybenefitinusingDOCK6inparallelmodeistoreducebookkeepingtasksassociatedwithmanuallysplittingupadatabaseintomultiplechunkswhichthenmustbesubmittedtodifferentprocessorsindividually.
DOCK6automaticallypartitionsoutsubsetsofadatabasetovariousprocessors,collatesandranksthefinalresults,andtakescareofallintermediatebookkeeping.
ParalleljobssimplyrequirethattheuserspecifythelocationoftheMPIprogramusedtocompileDOCK6,amachinefilelistingthenamesofthenodes,andthetotalnumberofprocessorstobeused.
Forparalleldockingthreeadditionalparametersmustbespecified:(1)thepathoftheMPICH2installation(i.
e/usr/local/mpich2-1.
0.
4/bin/mpirun),(2)amachinefilecontainingthenamesofthecomputers(nodes)tobeused,and(3)thenumberofprocessorswhichtypicallyisthesameasthenumberoflinesinthemachinefile.
SeeCommandlineArgumentsforusageinformationonhowtorunDOCKwithparallelprocessingfunctionality.
AccessoriesDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm45of659/18/20072:30PMRETURNTOTABLEOFCONTENTS3.
1.
GridAUTHOR:ToddEwing(basedonworkbyElaineMengandBrianShoichet)USAGE:grid-igrid.
in[-stv][-ogrid.
out]OPTIONS:-iinput_file#Inputparametersextractedfrominput_file,orgrid.
inifnotspecified-ooutput_file#Outputwrittentooutput_file,orgrid.
outifnotspecified-sInputparametersenteredinteractively-tReducedoutputlevel-vIncreasedoutputlevelDESCRIPTION:3.
1.
1.
OverviewGridcreatesthegridfilesnecessaryforrapidscoreevaluationinDOCK.
Twotypesofscoringareavailable:contactandenergyscoring.
Thescoringgridsarestoredinbinaryfilesendingin*.
cntand*.
nrgrespectively.
Whendocking,eachscoringfunctionisappliedindependentoftheothersandtheresultsarewrittentoseparateoutputfiles.
Gridalsocomputesabumpgridwhichidentifieswhetheraligandatomisinseverestericoverlapwithareceptoratom.
Thebumpgridisidentifiedwitha*.
bmpfileextension.
Thebinaryfilecontainingthebumpgridalsostoresthesize,positionandgridspacingofallthegrids.
Thegridcalculationmustbeperformedpriortodocking.
Thecalculationcantakeupto45minutes,butneedstobedoneonlyonceforeachreceptorsite.
Gridgenerationanddockingshouldbeperformedonthesameplatform;becausethegridfileshaveabinaryformat,copyinggridfilesbetweenmachinesmayproduceincorrectresults.
Furthermore,binaryfilesshouldnotbemodifiedwithtexteditors.
SinceDOCKcanperformcontinuumscoringwithoutagrid,thegridcalculationisnotalwaysrequired.
However,formostdockingtasks,suchaswhenmultiplebindingmodesforamoleculeormultiplemoleculesareconsidered,itwillbecomemoretimeefficienttoprecomputethescoringgrids.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
GeneralGridParameterscompute_grids[no](yes,no):DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm46of659/18/20072:30PM#Flagtocomputescoringgridsgrid_spacing[0.
3](float):#Thedistancebetweengridpointsalongeachaxis.
output_molecule[no](yes,no):#Flagtowriteoutthecoordinatesofthereceptorintoanew,cleaned-upfile.
Atomsare#resortedtoputallresidueatomstogetherreceptor_out_file[receptor_out.
mol2](string):#Fileforcleaned-upreceptorwhenoutput_moleculesetreceptor_file[receptor.
mol2](string):#Receptorcoordinatefile.
Partialchargesandatomtypesneedtobepresent.
box_file[site_box.
pdb](float):#FilecontainingSHOWBOXoutputfilewhichspecifiesboundariesofgridvdw_definition_file[vdw.
defn](string):#VDWparameterfile(seevdw.
defn)score_grid_prefix[grid](string):#Prefixforfilenameofgrids.
Fileextensionwillbeappendedautomatically.
RETURNTOTABLEOFCONTENTS3.
1.
2.
BumpCheckingPriortoscoring,eachorientationcanbeprocessedwiththebumpfiltertorejectonesthatpenetratedeepintothereceptor.
Orientationsthatpassthebumpfilterarethenscoredand/orminimizedwithanyoftheavailablescoringfunctions.
AbumpisbasedonthesumofthevanderWaalsradiiofthetwointeractingatoms.
Theuserspecifieswhatfractionofthesumisconsideredabump.
Forexample,thedefaultdefinitionofabumpisifanytwoatomsapproachcloserthan0.
75ofthesumoftheirradii.
Gridstoresanatomicradiuswhichcorrespondstosmallestradiusofligandatomatthegridpositionwhichwouldstilltriggerabump.
Duringdocking,foragivenorientation,thepositionofeachatomischeckedwiththebumpgrid.
Iftheradiusoftheatomisgreaterthanorequaltotheradiusstoredinthebumpgrid,thentheatomtriggersabump.
Toconservediskspace,theatomradiusismultipliedby10andconvertedtoashortunsignedinteger.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
BumpGridParametersbump_filter[no](yes,no):#Flagtoscreeneachorientationforclasheswithreceptorpriortoscoringandminimizingbump_overlap[0.
75](float):#AmountofVDWoverlapallowed.
IftheprobeatomandtheDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm47of659/18/20072:30PMreceptorheavyatomapproach#closerthanthisfractionofthesumoftheirVDWradii,thenthepositionisflaggedasa#bump0=Completeoverlapallowed1=NooverlapallowedRETURNTOTABLEOFCONTENTS3.
1.
3.
ContactScoringContactscoringingridincorporatesthescoringperformedwiththeDISTMAPprogram(developedbyShoichetandBodian).
Thescoreisasummationoftheheavyatomcontacts(everyatomexcepthydrogen)betweentheligandandreceptor.
Acontactisdefinedasanapproachoftwoatomswithinsomecutoffdistance(usually4.
5Angstroms).
Ifthetwoatomsapproachcloseenoughtobump(asidentifiedwiththebumpgrid)thentheinteractioncanbepenalizedbyanamountspecifiedbytheuser.
DistancedependenceofcontactscorefunctionTheattractivescoreingridisnegativeandarepulsivescoreispositive.
Thisswitchofsignisnecessarytoallowthesameminimizationprotocoltobeusedforcontactscoringasimplementedforenergyscoring.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
ContactGridParametersDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm48of659/18/20072:30PMcontact_score[no](yes,no):#Flagtoconstructcontactgridcontact_cutoff_distance[4.
5](float):#MaximumdistancebetweenheavyatomsfortheinteractiontobecountedasacontactRETURNTOTABLEOFCONTENTS3.
1.
4.
EnergyscoringTheenergyscoringcomponentofDOCKisbasedontheimplementationofforcefieldscoring.
Forcefieldscoresareapproximatemolecularmechanicsinteractionenergies,consistingofvanderWaalsandelectrostaticcomponents:whereeachtermisadoublesumoverligandatomsiandreceptoratomsj,whichincludethequantitieslistedbelow.
GeneralizationoftheVDWcomponentThevanderWaalscomponentofthescoringfunctionhasbeengeneralizedtohandleanycombinationofrepulsiveandattractiveexponents(providingthata>b).
Theusermaychooseto"soften"thepotentialbyusinga6-9Lennard-Jonesfunction.
ThegeneralformofthevanderWaalsinteractionbetweentwoidenticalatomsispresented:whereeisthewelldepthoftheinteractionenergy,RisthevanderWaalsradiusoftheatoms,andcoefficientsCandDcanbedeterminedgiventhetwofollowingboundaryconditions:atatApplicationoftheseboundaryconditionstotheaboveequationyieldsanexpressionofthevanderWaalsinteractionwithageneralizedLennard-Jonespotential.
TheconsequenceofusingadifferentexponentfortherepulsivetermDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm49of659/18/20072:30PMisillustratedinFigure1.
Noticethatthewellpositionanddepthareunchanged,butthattherepulsivebarrierhasshrunkbyabouta0.
25Angstrom.
DistancedependenceoftheLennard-JonesFunctionPrecomputingpotentialsonagridByinspectionoftheaboveequations,therepulsionandattractionparameters(AijandBij)fortheinteractionsofidenticalatomscanbederivedfromthevanderWaalsradius,R,andthewelldepth,e.
Inordertoevaluatetheinteractionenergyquickly,thevanderWaalsandelectrostaticpotentialsareprecomputedforthereceptorandstoredonagridofpointscontainingthedockingsite.
PrecomputingthevanderWaalspotentialrequirestheuseofageometricmeanapproximationfortheAandBterms,asshown:Usingthisapproximation,thefirstequationcanberewritten:DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm50of659/18/20072:30PMThreevaluesarestoredforeverygridpointk,eachasumoverreceptoratomsthatarewithinauserdefinedcutoffdistanceofthepoint:Thesevalues,withtrilinearinterpolation,aremultipliedbytheappropriateligandvaluestogivetheinteractionenergy.
Gridcalculatesthegridvaluesandstorestheminfiles.
ThevaluesarereadinduringaDOCKrunandusedforforcefieldscoring.
Theuserdeterminesthelocationanddimensionsofthegridboxusingtheprogramshowbox(seeshowbox).
Itisnotnecessaryforthewholereceptortobeenclosed;onlytheregionswhereligandatomsmaybeplacedneedtobeincluded.
Theboxmerelydelimitsthespacewheregridpointsarelocated,anddoesnotcausereceptoratomstobeexcludedfromthecalculation.
Besidesadirectspecificationofcoordinates,thereisanoptiontocenterthegridatasphereclustercenterofmass.
Anycombinationofspacingandx,y,andzextentsmaybeused.
NOTE:Thefollowingparameterdefinitionswillusetheformatbelow:parameter_name[default](value):#descriptionInsomecases,parametersareonlyneeded(questionswillonlybeasked)iftheparameteraboveisenforced.
Theseparametersareindicatedbelowbyadditionalindentation.
EnergyGridParametersenergy_score[no](yes,no):#Flagtoperformenergyscoringenergy_cutoff_distance[10](float):#Maximumdistancebetweentwoatomsfortheircontributiontotheenergyscoretobe#computedDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm51of659/18/20072:30PMatom_model[u](u,a):#Flagforhowtomodelofnonpolarhydrogensu=Unitedatommodel.
HydrogensattachedtocarbonsareassignedazeroVDWwell-depthandthepartialchargeistransferredtothecarbon.
a=Allatommodel.
HydrogensattachedtocarbonshaveregularVDWwell-depthandpartialchargeisnotmodified.
attractive_exponent[6](int):#ExponentofattractiveLennard-JonestermforVDWpotentialrepulsive_exponent[12](int):#RepulsiveofattractiveLennard-JonestermforVDWpotentialdistance_dielectric[yes](yes,no):#Flagtomakethedielectricdependlinearlyonthedistancedielectric_factor[4.
0](float):#CoefficientofthedielectricRETURNTOTABLEOFCONTENTS3.
2.
DocktoolsDocktoolsisasuiteofprogramsthatareavailabletocreategridsusedbyDock3.
5scorefunctioninDOCK6whichisanimplementationofthescoringfunctionavailableintheolderversionofDOCKi.
e.
,dock3.
5.
54.
Theseprogramscanbeusedtogeneratesteric,electrostaticandligandandreceptordesolvationgrids.
Dock3.
5scoringfunctionalityinDOCK6isanalternatescoringapproachtoelectrostaticinteractionenergyandalsoincludesdifferentgrid-basedmethodsforcalculatingligandandreceptordesolvation.
Docktoolsconsistsofchemgrid,solvmap,solvgrid,grid-convertandgrid-convrds.
Thissectionwillbrieflyreviewthetheorybehindeachoftheprogramsandthedescribetheusage.
3.
2.
1.
CHEMGRIDAUTHOR:BrianK.
ShoichetDESCRIPTION:Thisprogramchemgridproducesvaluesforcomputingforcefieldscoresandbumpchecking.
Theforcefieldscores,ormolecularmechanicsinteractionenergiesarecalculatedasvanderWaalsandelectrostaticcomponentsandstoredongrids.
ThecalculationsarebasedonthetheorypresentedintheGridsectionabove.
HoweveronlythestericinteractionenergygridsareusedinDOCK6asapartofDock3.
5Score.
TheelectrostaticinteractioncalculationdiffersfromEnergyScoringinthefollowingaspects.
Forcalculatingtheelectrostaticinteraction,theelectrostaticpotentialofthereceptorcalculatedusingthelinearizedformofPoisson-Boltzmannequation:DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm52of659/18/20072:30PMWherephi(x)thepotentialisdeterminedbythedielectricfunctionepsilon(x),amodifiedDebye-Huckelparameterkappa(x),andthechargedensityofthereceptorrho(x).
Theelectrostaticpotentialmap(orphimap)iscalculatedusingDelPhiandthenisusedbyDOCK6tocalculatetheelectrostaticinteractionenergyas:Where,qithepartialchargeofeveryatomi,ismultipliedbytheelectrostaticpotentialofthereceptorphiattherespectiveatomicposition.
Trilinearinterpolationmethodisusedforinterpolatingtheelectrostaticpotentialfromthephimapontotheligandposition.
USAGE:chemgridINPUTFILE:ThisprogramsrequirethatanINCHEMfilebecreatedintheworkingdirectory,whichcontainstheparameterstocontroltheprogram.
TheINCHEMparametersforchemgridaredetailedbelow:receptor.
pdb;receptorpdbfileparameters/prot.
table.
ambcrg.
ambH;chargeparameterfileparameters/vdw.
parms.
amb.
mindock;VDWparameterfilebox.
pdb;boxpdbfile0.
33;gridspacinginangstroms1;estype:distance-dependentdielectric;2:constantdielectric1;esscaleforffscoring2.
32.
8;bumpingdistancesforpolarandnon-polarreceptoratomsoutput_prefix;outputgridprefixnameOUTPUTFILESOUTCHEM#restatementofinputparameters;messagespertainingtocalculationofthegridsOUTPARM#messagespertainingtoparameterizationofreceptoratoms;netchargeonthereceptormoleculeincludinganyionsorwatersinthereceptorpdbfilePDBPARM#showswhichparametershavebeenassociatedwitheachatominthereceptorpdbfileoutput_prefix.
bmp#bumpgridoutput_prefix.
vdw#vdwvaluesforreceptoroutput_prefix.
es#electrostaticvaluesforreceptor3.
2.
2SOLVMAPAUTHOR:BrianK.
ShoichetDESCRIPTION:DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm53of659/18/20072:30PMThesolvmapprogramcalculatesthegridthatisusedbyDOCK6forcalculatingliganddesolvation.
Liganddesolvationiscalculatedasasumoftheatomicdesolvationmultipliedbyanormalizationfactorthataccountsfortheextenttowhichtheligandatomisburiedbythebindingsite.
TheatomicdesolvationforeachligandatomcanbecalculatedbyAMSOL(AMSOLisnotdistributedbyus,pleasefollowthelinkformoreinformation)andisstoredintheinputfile(seefileformats).
Thecostofdesolvatingeachatom,orthenormalizationfactor,isthedistanceweightedhighdielectricvolumedisplacedbytheproteinthatisstoredforeachgridelementintheactivesite.
Thusthevolumebasedliganddesolvationenergyiscalculatedas:HereListheligandatomdesolvation,volumesummedoverkvolumeelements,V.
ThismethodisonlyanapproximationtoGBsolvationandworkswithinthelimitsofcompleteburialfromthesolventandcompleteexposuretothesolventontheproteinsurface.
However,beinggrid-baseditisfastandcanbeusedduringconformationalsearchandfinalscoring.
USAGE:solvmapINPUTFILE:ThisprogramsrequirethatanINSOLVfilebecreatedintheworkingdirectory,whichcontainstheparameterstocontroltheprogram.
TheINSOLVparametersforchemgridaredetailedbelow:receptor.
pdb;receptorfilesolvmap;outputgridfile1.
4,1.
3,1.
7,2.
2,2.
2,1.
8;radiiofoxygen,nitrogen,carbon,sulfur,phosphorus,and"other"atoms.
1.
4;radiusofprobe1;gridresolutionbox.
pdb;boxfileOUTPUTFILES:OUTSOLV#restatementofinputparameters;messagespertainingtocalculationofthegridssolvmap#liganddesolvationgrids3.
2.
3SOLVGRIDAUTHORKaushikRahaDESCRIPTION:Thesolvgridprogramcreatesbulk(orreceptor)andexplicit(orligand)DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm54of659/18/20072:30PMdesolvationgridsusingtheoccupancydesolvationmethod(Lutyet.
al.
,J.
Comp.
Chem,1995;Verkhiveret.
al.
,J.
Mol.
Recog.
,1999).
Theoccupancydesolvationmethodisphenomenonlogicalinnaturewheredesolvationenergycanbedescribedpairwiseadditively.
Thedesolvationenergyduetointeractionbetweenaligandatomandreceptoratomcanbecalculatedasthesolventaffinityofaligandatomweightedbythevolumeofthesolventdisplacedfromthereceptoratomduetobindingandviceversa.
Thus,Edsol=SiDES,EXPL(xi)+fiDES,BULK(xi)Wherethemobileatomi,hasasolvationaffinityofSiandafragmentalvolumeoffi.
Thesolventaffinityoftheligandatomiscalculatedas:Whereqiisthechargeontheligandatomi,andalphaandbetaareconstantssetatalpha=0.
25kcal/molandbeta=-0.
005kcal/mol.
fiisthevolumeofligandatomi,calculatedfromtheamberradiusoftheligandatom.
Forthereceptor,thesecanbeprecalculatedandstoredonagrid.
DES,BULK(xi)andDES,EXPL(xi)areinterpolatedfromgridscalculatedusingthesolvgridprogramduringdocking.
Itrequiresthecalculationoftwoseparategrids:wherejisarigidreceptoratom,andSjandfjarethesolventaffinityandthefragmentalvolumeofthereceptoratomrespectively.
BulkandexplicitdesolvationgridsarecalculatedfromfjandSjatgridpointsp,distancerjpfromthereceptoratommultipliedbygaussianweightingofthedistance.
Thesolvgridprogramcalculatesthesegridsfromthechargeandthevolumeofthereceptoratoms.
USAGE:solvgridINPUTThisprogramsrequirethatanINRDSLfilebecreatedintheworkingdirectory,whichcontainstheparameterstocontroltheprogram.
TheINRDSLparametersforsolvgridaredetailedbelow:receptor.
pdb;receptorpdbfileparameters/prot.
table.
ambcrg.
ambH;chargeparameterfileDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm55of659/18/20072:30PMparameters/vdw.
parms.
amb.
mindock;VDWparameterfilebox.
pdb;boxpdbfile0.
33;gridspacinginangstroms1;estype:distance-dependentdielectric;2:constantdielectric4;esscaleforffscoring2.
32.
8;bumpingdistancesforpolarandnon-polarreceptoratomsoutput_prefix;outputgridprefixnamesol_op;methodforcalculatingdesolvationgridsolE_recep;solvationfreeenergyofreceptorOUTPUTFILESOUTRDSL#restatementofinputparameters;messagespertainingtocalculationofthegridsOUTPARM#messagespertainingtoparameterizationofreceptoratoms;netchargeonthereceptormoleculeincludinganyionsorwatersinthereceptorpdbfilePDBPARM#showswhichparametershavebeenassociatedwitheachatominthereceptorpdbfileoutput_prefix.
bmp#bumpgridoutput_prefix.
vdw#vdwvaluesforreceptoroutput_prefix.
es#electrostaticvaluesforreceptoroutput_prefix.
dsl#bulkandexplicitdesolvationgridforreceptor3.
2.
4GRID-CONVERTAUTHOR:KaushikRaha,JohnJ.
Irwin(DerivedfromToddEwing'sGRIDProgram)DESCRIPTION:Thisconsistsofprogramsgrid-convertandgrid-convrdsthatconvertgridsgeneratedbychemgrid,solvgridandDelPhiintoDOCK6readablegrids.
USAGE:grid-convert-igconv.
in>&gconv.
outINPUTFILES:gconv.
in;inputfilewithparametersvdw.
defn;vdwparametersfileconv.
defn;atomtypedefinitionfileRETURNTOTABLEOFCONTENTS3.
3.
NchemgridsAUTHOR:XiaoqinZouUSAGE:nchemgrid_GBornchemgrid_SADOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm56of659/18/20072:30PMINPUTFILE:BothprogramsrequirethatanINCHEMfilebecreatedintheworkingdirectory,whichcontainstheparameterstocontroltheprogram.
TheINCHEMparametersforboththenchemgrid_GBandnchemgrid_SAprogramsaredetailedbelow:Fornchemgrid_GB:receptor.
pdb;receptorpdbfilecavity.
pdb;cavitypdbfileparameters/prot.
table.
ambcrg.
ambH;chargeparameterfileparameters/vdw.
parms.
amb;VDWparameterfilebox.
pdb;boxpdbfile0.
4;gridspacinginangstroms2;estype:GB1;esscaleforffscoring8.
08.
0;cutoffforesandouterbox78.
378.
3;dielectricofsolvent,cavity2.
32.
8;bumpingdistancesoutput_prefix;outputgridprefixname1;pairwisecalculationNOTE:Thecavity.
pdbfileshouldbeanemptyfile.
Thisfeatureisnotfrequentlyused.
However,theparametermuststillbepassed.
Thepairwisecalculationvaluemustalsoalwaysbe1.
Fornchemgrid_SA:receptor.
pdb;receptorpdbfileparameters/prot.
table.
ambcrg.
ambH;chargeparameterfileparameters/vdw.
parms.
amb;VDWparameterfilebox.
pdb;boxpdbfile0.
4;gridspacinginangstroms1.
4;proberadiusforSA2;scoringtype:SA8.
0;cutoffforSAcalculationsoutput_prefix;outputgridprefixnameDESCRIPTION:Thenchemgrid_gbandnchemgrid_saprogramscreatetheGBandSAreceptorgridsforusewiththeZouGB/SAscoringfunction(seeZouGB/SAScoring).
OUTPUTFILESFornchemgrid_gbinva#debuggingfilewithinverseBornradiusforreceptoratomsNEG_INVA#errorfilelistingembeddedreceptoratomsOUTCHEM#restatementofinputparameters;messagespertainingtocalculationofthegridsOUTPARM#messagespertainingtoparameterizationofDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm57of659/18/20072:30PMreceptoratoms;netchargeonthereceptormoleculeincludinganyionsorwatersinthereceptorpdbfilePDBPARM#showswhichparametershavebeenassociatedwitheachatominthereceptorpdbfilescreen.
para#filethatcontainsdescreeningparameterszou_grid.
bmp#bumpgridzou_grid.
rec#xyzcoordinates,effectivecharge,effectivevdwradii,inverseBornradii,anddescreeningparametersforreceptorzou_grid.
sol#flagsforwhetherreceptoratomsaresolvatedzou_grid.
vdw#vdwvaluesforreceptorFornchemgrid_sa:OUTCHEM#restatementofinputparameters;messagespertainingtocalculationofthegridsOUTPARM#messagespertainingtoparameterizationofreceptoratoms;netchargeonthereceptormoleculeincludinganyionsorwatersinthereceptorpdbfilePDBPARM#showswhichparametershavebeenassociatedwitheachatominthereceptorpdbfilezou_grid.
bmp#bumpgridzou_grid.
sas#xyzcoordinates,effectivevdwradii,vdwtype,numberofsphericalgridpoints,andpolaritytypeforeachreceptoratomzou_grid.
sasmark#informationaboutgridspacing,coordinates,dimensions,etcRETURNTOTABLEOFCONTENTS3.
4.
SphgenAUTHOR:IrwinD.
Kuntz(modifiedbyReneeDesJarlaisandBrianShoichet)USAGE:sphgenINPUTFILE*:rec.
ms#molecularsurfacefileR#sphereoutsideofsurface(R)orinsidesurface(L)X#specifiessubsetofsurfacepointstobeused(X=allpoints)0.
0#preventsgenerationoflargesphereswithclosesurfacecontacts(default=0.
0)4.
0#maximumsphereradiusinAngstroms(default=4.
0)1.
4#minimumsphereradiusinAngstroms(default=radiusofprobe)rec.
sph#clusteredspheresfile*WARNINGS:(1)TheinputfilenamesandparametersarereadfromafilecalledINSPH,whichshouldnotcontainanyblanklinesorthecomments(denotedby#)fromabove.
(2)Themolecularsurfacefilemustincludesurfacenormals.
SPHGENexpectstheFortranformatA3,I5,X,A4,X,2F8.
3,F9.
3,X,A3,7X,3F7.
3DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm58of659/18/20072:30PMDESCRIPTION:3.
4.
1.
OverviewSphgengeneratessetsofoverlappingspherestodescribetheshapeofamoleculeormolecularsurface.
Forreceptors,anegativeimageofthesurfaceinvaginationsiscreated;foraligand,theprogramcreatesapositiveimageoftheentiremolecule.
SpheresareconstructedusingthemolecularsurfacedescribedbyRichards(1977)calculatedwiththeprogramdms.
Eachspheretouchesthemolecularsurfaceattwopointsandhasitsradiusalongthesurfacenormalofoneofthepoints.
Forthereceptor,eachspherecenterisoutsidethesurface,andliesinthedirectionofasurfacenormalvector.
Foraligand,eachspherecenterisinsidethesurface,andliesinthedirectionofareversedsurfacenormalvector.
Spheresarecalculatedovertheentiresurface,producingapproximatelyonespherepersurfacepoint.
Thisverydenserepresentationisthenfilteredtokeeponlythelargestsphereassociatedwitheachreceptorsurfaceatom.
Thefilteredsetisthenclusteredonthebasisofradialoverlapbetweenthespheresusingasinglelinkagealgorithm.
Thiscreatesanegativeimageofthereceptorsurface,whereeachinvaginationischaracterizedbyasetofoverlappingspheres.
Thesesets,orclusters,aresortedaccordingtonumbersofconstituentspheres,andwrittenoutinorderofdescendingsize.
Thelargestclusteristypicallytheligandbindingsiteofthereceptormolecule.
TheprogramshowspherewritesoutspherecentercoordinatesinPDBformatandmaybehelpfulforvisualizingtheclusters(seeshowsphere).
RETURNTOTABLEOFCONTENTS3.
4.
2.
CriticalPointsTheprocessoflabelingsitepointsforcriticalmatchingmustcurrentlybedonebyhand(seeCriticalPointsforuseinDOCK).
Theusershouldloadthesitepointsandthereceptorcoordinatesintoagraphicprogramtodeterminethespheresclosesttothetargetarea.
Onceasphereorgroupofsphereshasbeendeterminedtobecritical,thesphere(s)shouldbelabeledbychangingthesecondtolastcolumnofthefinalspherefiletothecriticalclusternumber(seeOutput).
RETURNTOTABLEOFCONTENTS3.
3.
3.
ChemicalMatchingTheprocessoflabelingsitepointsforchemicalmatchingmustalsobedonebyhand(seeChemicalMatchingforuseinDOCK).
Theusershouldloadthesitepointsandthereceptorcoordinatesintoagraphicprogramandstudythelocalenvironmentofeachpoint.
LabeledsitepointsmaybeinputaseitheraSPHformatorSYBYLMOL2formatcoordinatefile.
TostorelabeledsitepointsinaMOL2file,selectanatomtypeforeachlabelofinterest.
ThenedittheDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm59of659/18/20072:30PMchem.
defnfiletoincludetheselectedatomtypes(seechem.
defn).
Sitepointdefinitionscanbedistinguishedfromligandatomdefinitionsbyexplicitlyrequiringthatnobondedatomscanbeattached(ie.
followedby[*]).
Usingtheconventioninthatexamplefile,sitepointsshouldbelabeledasfollows:hydrophobic,"C.
3";donor,"N.
4";acceptor,"O.
2";polar,"F".
ExampleofchemicallabelsinSPHformatDOCK3.
5receptor_spherescolorhydrophobic1coloracceptor2colordonor3cluster1numberofspheresincluster4972.
3450036.
4900016.
935001.
5000018-0.
0520042.
2990014.
188001.
5000019-0.
6700041.
2060011.
598001.
50000117-6.
0000034.
0000017.
000001.
50000318-5.
0000029.
0000022.
000001.
500013.
.
.
CaveatsonChemicalMatchingItcantakeasignificantamountofefforttochemicallylabelalargesiteandtoverifythatthedockingresultsarewhatwereexpected.
Ifyouusethischemicalmatching,plantospendsometimeinpreparationandvalidationBEFORErunninganentiredatabaseofmolecules.
Itmustbepointedoutthattheultimatearbiterofwhichorientationsofaligandaresavedisactuallythescoringfunction.
Ifthescoringfunctionisunabletodiscriminatewhattheuserfeelsarebadchemicalinteractions,thenanyimprovementwithchemicalmatchingwillprobablybeobscured.
Inaddition,ifscoreoptimizationisused,thentheorientationwillbeperturbedfromtheoriginalchemically-matchedpositiontoanewscore-preferredpositions.
RETURNTOTABLEOFCONTENTS3.
4.
4.
OutputSomeinformativemessagesarewrittentoafilecalledOUTSPH.
Thisincludestheparametersandfilesusedinthecalculation.
Thespheresthemselvesarewrittentotheclusteredspheresfile.
Theyarearrangedinclusterswiththeclusterhavingthelargestnumberofspheresappearingfirst.
ThesphereclusterfileconsistsofaheaderfollowedDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm60of659/18/20072:30PMbyaseriesofsphereclusters.
TheheaderisthelineDOCK3.
5receptor_spheresfollowedbyacolortable(seeChemicalMatching).
Thecolortablecontainscolornameseachonaseparateline.
Assphgenproducesnocolors,thecolortableissimplyabsent.
Thesphereclustersthemselvesfollow,eachofwhichstartswiththelineclusternnumberofspheresinclusteriwherenistheclusternumberforthatspherecluster,andiisthenumberofspheresinthatcluster.
Next,allspheresinthatclusterarelistedintheformatbelow:FORMAT:(I5,3F10.
5,F8.
3,I5,I2,I3)I:IntegerF:Float012345012345678901234567890123456789012345678901234567890123456789635.
5840550.
9100559.
970291.
4119200649.
0037852.
4615962.
309261.
400321006611.
4368556.
4971561.
790081.
98449300I5:Column0~4(thefirst5columns)wereusedtoputintegerdata.
F10.
5:Column5~14(total10columns,and5digitsformantissa)wereusedtoputfloatdata.
Thevaluesinthespherefilecorrespondto:Thenumberoftheatomwithwhichsurfacepointi(usedtogeneratethesphere)isassociated.
Thex,y,andzcoordinatesofthespherecenter.
Thesphereradius.
Thenumberoftheatomwithwhichsurfacepointj(secondpointusedtogeneratethesphere)isassociated.
Thecriticalclustertowhichthisspherebelongs.
Thespherecolor.
Thecolorissimplyanindexintothecolortablethatwasspecifiedintheheader.
Therefore,1correspondstothefirstcolorintheheader,2forthesecond,etc.
0correspondstounlabeled.
Theclustersarelistedinnumericalorderfromlargestclusterfoundtothesmallest.
Attheendoftheclustersisclusternumber0.
Thisisnotanactualspherecluster,butalistofallofthespheresgeneratedwhoseradiiwerelargerthantheminimumradius,beforethefilteringheuristics(i.
e.
allowingonlyonesphereperatomandusingamaximumradiuscutoff)andclusteringwereperformed.
Cluster0maybeusefulasastartingpointforuserswhowanttoexploreawiderrangeofpossibleclustersthanisprovidedbythestandardSPHGENclusteringroutine.
Theprogramcreatesthreetemporaryfiles:temp1.
ms,temp2.
sph,andtemp3.
atc.
TheseareusedinternallybySPHGEN,andaredeleteduponcompletionofthecomputation.
Formoreinformationonspheregenerationandselection,gototheSphereGenerationandSelectiondemo.
DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm61of659/18/20072:30PMRETURNTOTABLEOFCONTENTS3.
5.
ShowboxAUTHOR:ElaineMengUSAGE:showbox[DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm62of659/18/20072:30PMSphere_selectorwilltaketheouputfromspghenandselectallsphereswithauser-definedradiusofatargetmolecule(seesphgen).
Thetargetmoleculecanbeanything(ieknownligand,receptorresidue,etc)aslongasitisinproperMOL2format.
WARNING:Pleasenotethataboveorderofinputfilesmustbemaintainedfortheprogramtowork.
RETURNTOTABLEOFCONTENTS3.
8.
AntechamberAntechamberisanaccessoryprogramoriginallydevelopedtopreparesmallmoleculesontheflytouseinAMBER.
Withpermission,wehaveincludedadistributionofthecodetofacilitatepreparingsmallmoleculesforAmber_Score.
Formoreinformationontheuseoftheantechamberaccessory,pleasevisitthesourcewebsiteatamber.
scripps.
edu/antechamber/antechamber.
html.
Fromthewebsite:"Antechamberisasetofauxiliaryprogramsformolecularmechanic(MM)studies.
ThissoftwarepackageisdevotedtosolvethefollowingproblemsduringtheMMcalculations:(1)recognizingtheatomtype;(2)recognizingbondtype;(2)judgingtheatomicequivalence;(3)generatingresiduetopologyfile;(4)findingmissingforcefieldparametersandsupplyingreasonableandsimilarsubstitutes.
Asanaccessorymodule.
.
.
,antechambercangenerateinputautomaticallyformostorganicmoleculesinadatabase.
.
.
.
"RETURNTOTABLEOFCONTENTSMolecularFileFormatsRETURNTOTABLEOFCONTENTS4.
1.
TriposMOL2FormatThisformatisusedforgeneralmoleculeinputandoutputofDOCK.
AlthoughpreviousversionsofDOCKsupportedanextendedPDBformattostoremoleculeinformation,thecurrentversionnowusesMOL2asthemoleculeformat.
Thisformathastheadvantageofstoringallthenecessaryinformationforatomfeatures,position,andconnectivity.
Itisalsoastandardizedformatthatothermodelingprogramscanread.
FormoreinformationonhowtogenerateMOL2filesfromPDBfiles,gototheStructurePreparationdemo.
OfthemanyrecordtypesinaMOL2file,DOCKrecognizestheDOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm63of659/18/20072:30PMfollowing:MOLECULE,ATOM,BOND,SUBSTRUCTUREandSET.
IntheMOLECULErecord,DOCKutilizesinformationaboutthemoleculenameandnumberofatoms,bonds,substructuresandsets.
IntheATOMrecordDOCKutilizesinformationabouttheatomnames,types,coordinates,andpartialcharges.
IntheBONDrecord,DOCKutilizestheatomidentifiersforthebond.
IntheSUBSTRUCTURErecord,DOCKrecordsthefields,butdoesnotutilizethem.
TheSETrecordsareentirelyoptional.
Theyareusedonlyinspecialcircumstances,likewhenligandflexibilityisconsidered.
InDOCK6,anadditionalrecordtypehasbeenintroduced.
ThisistheSOLVATIONrecord,thathastheatomicdesolvationinformationfortheligandatoms.
Theparameterread_mol_solvationcanbeusedtoreadinthisrecord.
ForextensivedetailsontheMOL2format,aswellasexamplefiles,pleaserefertotheTriposwebsitedocumentation(http://www.
tripos.
com/data/support/mol2.
pdf).
RETURNTOTABLEOFCONTENTS4.
2.
PDBFormatThisformatisusedforseveraloftheDOCKaccessoriesandtheAMBERscorefunction.
ForextensivedetailsonthePDBformat,aswellasexamplefiles,pleaserefertotheProteinDatabankFileFormatDocumentation(http://www.
pdb.
org/pdb/static.
dop=file_formats/pdb/index.
html).
RETURNTOTABLEOFCONTENTS5.
ReferencesDesJarlais,R.
L.
andDixon,J.
S.
AShape-andchemistry-baseddockingmethodanditsuseinthedesignofHIV-1proteaseinhibitors.
J.
Comput-AidedMolec.
Design.
8:231-242,1994.
Ewing,T.
J.
A.
andKuntz,I.
D.
,Criticalevaluationofsearchalgorithmsforautomatedmoleculardockinganddatabasescreening.
J.
Comput.
Chem.
18:1175-1189,1997.
Ferro,D.
R.
andHermans,J.
Differentbestrigid-bodymolecularfitroutine.
Acta.
Cryst.
A.
33:345-347,1977.
Hawkins,G.
D.
;Cramer,C.
J.
;Truhlar,D.
G.
PairwiseSoluteDescreeningofSoluteChargesfromaDielectricMedium.
Chem.
Phys.
Lett.
246:122-129,1995Hawkins,G.
D.
;Cramer,C.
J.
;Truhlar,D.
G.
Parametrizedmodelsofaqueousfreeenergiesofsolvationbasedonpairwisedescreeningofsoluteatomicchargesfromadielectricmedium.
J.
Phys.
Chem.
100:19824-19839,1996Irwin,J.
J.
andShoichet,B.
K.
ZINC-Afreedatabaseofcommerciallyavailablecompoundsforvirtualscreening.
J.
Chem.
Inf.
Model.
45:177-182,2005.
Kollman,P.
A.
;Massova,I.
;Reyes,C.
;Kuhn,B.
;Huo,S.
;Chong,L.
;DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm64of659/18/20072:30PMLee,M.
;Lee,T.
;Duan,Y.
;Wang,W.
;Donini,O.
;Cieplak,P.
;Srinivasan,J.
;Case,D.
A.
;Cheatham,T.
E.
,Calculatingstructuresandfreeenergiesofcomplexmolecules:combiningmolecularmechanicsandcontinuummodels.
Acc.
Chem.
Res.
33:889-897,2000Kuhl,F.
S.
,Crippen,G.
M.
,andFriesen,D.
K.
ACombinatorialAlgorithmforCalculatingLigandBinding.
J.
Comput.
Chem.
5:24-34,1984.
Kuntz,I.
D.
,Blaney,J.
M.
,Oatley,S.
J.
,Langridge,R.
andFerrin,T.
E.
Ageometricapproachtomacromolecule-ligandinteractions.
J.
Mol.
Biol.
161:269-288,1982.
Liu,H.
-Y.
,Kuntz,I.
D.
,andZou,X.
PairwiseGB/SAScoringFunctionforStructure-basedDrugDesign.
J.
Phys.
Chem.
B.
108:5453-5462,2004.
Luty,B.
A.
;WassermanP.
F.
;HodgeC.
N.
;ZachariasM.
;McCammonJ.
A.
AMolecularMechanics/GridMethodforEvaluationofLigand-ReceptorInteractions.
J.
Comput.
Chem.
16:454-464(1995)Meng,E.
C.
,Gschwend,D.
A.
,Blaney,J.
M.
andKuntz,I.
D.
Orientationalsamplingandrigid-bodyminimizationinmoleculardocking.
Proteins.
17(3):266-278,1993.
Meng,E.
C.
,Shoichet,B.
K.
andKuntz,I.
D.
Automateddockingwithgrid-basedenergyevaluation.
J.
Comp.
Chem.
13:505-524,1992.
Miller,M.
D.
,Kearsley,S.
K.
,Underwood,D.
J.
andSheridan,R.
P.
FLOG-Asystemtoselectquasi-flexibleligandscomplementarytoareceptorofknownthree-dimensionalstructure.
J.
Comput.
AidedMol.
Design.
8:153-174,1994.
Moustakas,D.
T.
,Lang,P.
T.
,Pegg,S.
,Pettersen,E.
T.
,Kuntz,I.
D.
,Broojimans,N.
,Rizzo,R.
C.
DevelopmentandValidationofaModular,ExtensibleDockingProgram:DOCK5.
J.
Comput.
AidedMol.
Design.
20:601-609,2006.
Nelder,J.
A.
andMead,R.
,ASimplex-MethodforFunctionMinimization.
ComputerJournal,7:308-313,1964.
Onufriev,A.
,Bashford,D.
,andCase,D.
A.
Exploringproteinnativestatesandlarge-scaleconformationalchangeswithamodifiedgeneralizedBornmodel.
Proteins.
55:383-394,2004.
Pearlman,D.
A.
,Case,D.
A.
,Caldwell,J.
W.
,Ross,W.
S.
,Cheatham,III,T.
E.
,DeBolt,S.
,Ferguson,D.
,Seibel,G.
andKollman,P.
A.
AMBER,apackageofcomputerprogramsforapplyingmolecularmechanics,normalmodeanalysis,moleculardynamicsandfreeenergycalculationstosimulatethestructuralandenergeticpropertiesofmolecules.
Comp.
Phys.
Commun.
91:1-41,1995.
Rizzo,R.
C.
;Aynechi,T.
;Case,D.
A.
;Kuntz,I.
D.
EstimationofAbsoluteFreeEnergiesofHydrationUsingContinuumMethods:AccuracyofPartialChargeModelsandOptimizationofNonpolarContributions.
J.
Chem.
TheoryComput.
2:128-139,2006DOCK6.
1UserManualhttp://dock.
compbio.
ucsf.
edu/DOCK_6/dock6_manual.
htm65of659/18/20072:30PMShoichet,B.
K.
,Bodian,D.
L.
andKuntz,I.
D.
Moleculardockingusingshapedescriptors.
J.
Comp.
Chem.
13(3):380-397,1992.
Shoichet,B.
K.
andKuntz,I.
D.
Proteindockingandcomplementarity.
J.
Mol.
Biol.
221:327-346,1991.
Srinivasan,J.
;Cheatham,T.
E.
;Cieplak,P.
;Kollman,P.
A.
;Case,D.
A.
,ContinuumsolventstudiesofthestabilityofDNA,RNA,andphosphoramidate-DNAhelices.
J.
Am.
Chem.
Soc.
120:9401-9409,1998.
Tsui,V.
andCase,D.
A.
Theoryandapplicationsofthegeneralizedsolvationmodelinmacromolecularsimulations.
Biopolymers.
56:275-291,2001.
Verkhiver,G.
M.
;Rejto,P.
A.
;Bouzida,D.
;Arthur,S.
;Colson,A.
B.
;et.
al.
TowardsUnderstandingtheMechanismsofMolecularRecognitionbyComputerSimulationofLigand-ProteinInteractions.
J.
Mol.
Recog.
12:371-389(1999)Wang,J.
,Wolf,R.
M.
,Caldwell,J.
W.
,Kollman,P.
A.
andCase,D.
A.
DevelopmentandtestingofageneralAmberforcefield.
J.
Comput.
Chem.
25:1157-1174,2004.
Weiser,J.
,Shenkin,P.
S.
,andStill,W.
C.
Approximateatomicsurfacesfromlinearcombinationsofpairwiseoverlaps(LCPO).
J.
Comput.
Chem.
20:217-230,1999.
Zou,X.
Q.
,Sun,Y.
X.
,andKuntz,I.
D.
Inclusionofsolvationinligandbindingfreeenergycalculationsusingthegeneralized-bornmodel.
J.
Am.
Chem.
Soc.
121(35):8033-8043,1999.
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