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Page 1: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

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D3RGrandChallenge2StructureRefinementExperience/LearningsStephenK.Burley,M.D.,D.Phil.Director,RCSBProteinDataBankMember,RutgersCancerInstituteofNewJerseyFoundingDirector,InstituteforQuantitativeBiomedicineDirector,CenterforIntegrativeProteomicsResearchDistinguishedProfessor,ChemistryandChemicalBiologyD3RWebinarMeetingMarch27th2017

Page 2: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Outline

§ ProteinDataBank(RCSBPDB,rcsb.org)§ RCSBPDBGroupDepositionSystem§ D3RStructureRePinementProtocol§ Experience/Learnings§ Acknowledgements

1

Page 3: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

ProteinDataBankArchive

§ PDB1stOpenAccessdigitaldataresourceinallofbiology

§ Founded1971with7X-raystructures

§ Today,singleglobalarchive

§ ManagedbywwPDBPartnership(RCSBPDB,PDBe,PDBj,BMRB)

2

Lysozyme!

Hemoglobin!

Ribonuclease!

Myoglobin!

Some of the very first structures in the PDB

Page 4: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

PDBFactsandFigures

§ >128,000StructuresArchivedsince1971§ ~11,500NewStructuresDeposited/Year§ ~30,000DepositorsWorldwide§ >1MillionUniqueUsersWorldwide/Year§ >550MillionDataFilesDownloaded/Year§ ~1.5MillionDataFilesDownloaded/Day§ USPDBHeadquarteredatRutgers/UCSD§ ~70%ofGlobalPDBUsagethroughRutgers/UCSD

3

Page 5: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

RCSBPDBGroupDeposiEonSystemhttps://deposit-group.rcsb.rutgers.edu/groupdeposit/ §  SupportsBatchDeposition/ValidationofRelatedStructures§  OriginallydevelopedforD3RBlindChallenges§  Todate,>1300structuresfromRoche,MerckSerono,BMS,SGC,etc.,with10s-100sofstructures/group

4

OneDep DepUI

Batch deposition: LogIn, Upload,

Download, Validation, Communication

Issue PDB & Dep ids

Status DB

Batch processing: Scripts/Special

treatment + stand-alone OneDep modules

OneDep Biocuration

DB Load

Release Module

wwPDB OneDep System

RCSB PDB GroupDep System

Page 6: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

D3RProtocol

§ D3RcompletesrePinements

§ GroupDepàPDB

§ PDBValidatesallrePinedstructures

§ ContributorsandD3Rco-authorPinalPDBdeposition

5

DataFilesfromContributors

D3RQACheck

Fail

Pass

ValidationOK?

D3RRePinement

PDBDeposition(GroupDep)

wwPDBValidationReport

FurtherProtein/LigandRePinement

D3RQualityReport

PDBHold/Release

D3RChallengeParticipants

Yes

No

FinalContributorReview

Page 7: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

D3RStructureRefinementProtocol

6

SFFiles(AnyFormat)

ModelFiles(CIF/PDB)

LigandRestraints(CIF)

Re+inementRefmac,

Phenix,Buster(various

parametersoptimized)

EDMapReview

(RSR,RSCC,RSZDforbackbone,sidechains)

wwPDBValidation(EDmaps,geometry,sequence,ligands)

Visualchecksofproblemareas

ManualcorrectionusingCOOT

Page 8: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

RocheFXRDataSetCharacterisEcs

§ 36Co-crystal/1ApoStructures•  ResolutionLimits:2.6-1.7Å•  AsymmetricUnitMWs:26-110kDa•  3PointGroups/5SpaceGroups

§ LigandMWs:219-564Da§ ThreeLigands:Bratoms§ FourLigands:AlternativeConformations§ AllLigands:BuriedinBindingPocket

7

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ProteinStructureQualityImproved

8

InitialRange FinalRange AverageChange

Rfree(%) 23.0-35.0 22.0-31.0 -1.0(better)Rwork(%) 17.0-30.0 18.0-25.0 <1.0(nochange)Rfree–Rwork(%) 4.0-11.0 3.0-10.0 -1.0(better)ClashScore 4.38-40.41 0.51-6.90 -15.16(better)RamachandranOutliers(%)

0.0-2.2 0.0-1.3 -0.3(better)

SidechainRotamerOutliers(%)

0.5-24.5 0.5-9.9 -7.9(better)

%RSRZOutliers 0.0-29.5 0.0-22.1 -2.2(better)BondsRMSZ 0.3-0.7 0.4-0.9 +0.2(worse)AnglesRMSZ 0.5-0.8 0.5-0.9 +0.1(worse)OverallQuality(%ileofarchive,seeShaoetal.2017)

0%-70% 5%-80% +25%(better)

Page 10: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

LigandStructureQualityImproved

9

Initial Final AverageChange

RSR(%) 8.0–21.0 7.0–19.0 -1.0(better)

RSCC(%) 82.0–98.0 79.0–98.0 +1.0(better)

BondLengthsOutliers

0–17 0-10 -3(better)

BondAnglesOutliers

3–24 0–7 -7(better)

Clashes 0-8 0-4 -1(better)

BondsRMSZ 0.8–2.9 0.5-2.9 -0.5(better)

AnglesRMSZ 1.1-3.1 0.5-2.0 -0.7(better)

RSZD+(absolute) 0.0-2.8 0.0-3.4 +0.2(balanced)

RSZD-(absolute) 0.0-4.2 0.0-3.3 -0.2(balanced)

Page 11: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

LigandGeometricalRestraints

10

§ Generatedligandrestraintswith•  AM1andRM1QMoptimizers

•  +/-Mogulvalues•  Variedplanaritysettings

§ BestresultswithAM1+Mogulandtighterplanarity,andmanualsettingofsomerestraintsasneeded

Roche1ymrc

Page 12: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Experience/Learnings:ParEalDisorder

11

Partialdisorderalternativeconformers(1dqzc,2.0Å)ThiophenealternativeconformationsCyclohexanedisorderedBlue:2|Fo|-|Fc|/1.0σ

Page 13: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Experience/Learnings:OverallDisorder

12

Entireligandintwoorientations(1txca,1.9Å)Blue:2|Fo|-|Fc|/1.0σ

Page 14: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Experience/Learnings:LossofBr

13

LigandwithBr(1xxar,1.8Å)Br-CbondoftenbrokenbyX-raybeamCrystalcontainstwoLigandspecies(+/-Br)BrModeledwithreducedOccupancyBlue:2|Fo|-|Fc|/1.5σRed:-ve|Fo|-|Fc|/3.0σGreen:+ve|Fo|-|Fc|/3.0σ

BrOccup=1.0 BrOccup=0.5

Page 15: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Experience/Learnings:AmbiguiEes

14

EDMapAmbiguity(fromdifferentstudy)Pseudo-symmetricligandsrequireinspectionofbindingenvironmentWrongOrientation!Blue:2|Fo|-|Fc|/1.0σ

Page 16: D3R Grand Challenge 2 Structure Refinement Experience/Learnings€¦ · D3R Webinar Meeting March 27th 2017 Outline § Protein Data Bank (RCSB PDB, rcsb.org) § RCSB PDB Group Deposition

Acknowledgements

§  HuanwangYang,ChenghuaShao,ZukangFeng,JohnWestbrook,JasmineYoung,EzraPeisach

§  SymonGathiaka,ShuaiLiu,MikeGilson,RommieAmmaro

15The RCSB PDB is funded by a grant from the National Science Foundation, the National Institutes of Health, and the US Department of Energy.


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