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rcsb.org D3R Grand Challenge 2 Structure Refinement Experience/Learnings Stephen K. Burley, M.D., D.Phil. Director, RCSB Protein Data Bank Member, Rutgers Cancer Institute of New Jersey Founding Director, Institute for Quantitative Biomedicine Director, Center for Integrative Proteomics Research Distinguished Professor, Chemistry and Chemical Biology D3R Webinar Meeting March 27 th 2017

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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

rcsb.org

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

Page 9: 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

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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