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OSPREY Tutorial Ivelin Georgiev Donald Lab Duke University.

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Presentation on theme: "OSPREY Tutorial Ivelin Georgiev Donald Lab Duke University."— Presentation transcript:

1 OSPREY Tutorial Ivelin Georgiev Donald Lab Duke University

2

3 Installation Setup Running OSPREY

4 Installation MPICH2mpiJavaJava 32-bit64-bit √ may require special instructions

5 Setup Input Structure Rotamer Library Energy Function Compute Nodes

6 mpirunjavaOSPREY Select MPI nodes: linux1 linux2 linux3 linux4 linux5 mpdboot mpdboot -n 5 -f mpd.hosts linux1 linux2 linux3 mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg Select job-specific nodes:

7 Input Structure missing atoms modeldelete REMARK 470 MISSING ATOM REMARK 470 THE FOLLOWING RESIDUES HAVE MISSING ATOMS (M=MODEL NUMBER; REMARK 470 RES=RESIDUE NAME; C=CHAIN IDENTIFIER; SSEQ=SEQUENCE NUMBER; REMARK 470 I=INSERTION CODE): REMARK 470 M RES CSSEQI ATOMS REMARK 470 GLU A 34 CG CD OE1 OE2 REMARK 470 GLU A 63 CD OE1 OE2 KiNG possible over-constraint possible under-constraint

8 Input Structure adding hydrogens general compounds proteins recommended: MolProbity recommended: Accelrys DS Visualizer Check: protonation states missing protons

9 Input Structure His residues HIPHIEHID

10 Input Structure steric shell close to design site significant speedup

11 Input Structure Other considerations: protein, ligand, cofactor ligand: natural AA, small molecule water molecules no chain ID’s unique residue numbers protein-peptide, protein-protein connectivity (good input structures)

12 Input Structure Check and double-check!!!

13 Rotamer Library rotamers general compounds proteins Richardsons’ Penultimate TYR 2 4 N CA CB CG CA CB CG CD TYR 2 5 N CA CB CG CA CB CG CD FCL 2 4 N CA CB CG CA CB CG CD one rotamer 11 22 name # dihed # rot

14 Energy Function parm96a.datall_amino94X.inall_nuc94_and_gr.in atom types dihedral parameters vdW parameters add params for new atom types antechamber amino acids partial charges connectivity typically no changes can modify partial charges general compounds partial charges connectivity add params for new compounds antechamber user control: distance-dependent dielectric, dielectric value, vdW radii scaling, solvation energy scaling, dihedral energies switch

15 Running OSPREY Ensemble-based Residue entropy GMEC-based

16 mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg input structure rotamer library energy function mutation search parameters energy minimization (MinDEE, BD, B RDEE ) DACS doDEE 1 MET GLY ASP ARG FCL unMinE: minE: bestE: MET GLY ASP MET FCL unMinE: minE: bestE: MET GLY ASP ARG FCL unMinE: minE: bestE: MET GLY SER ARG FCL unMinE: minE: bestE: MET GLY SER ARG FCL unMinE: minE: bestE:

17 GMEC-based java -Xmx1024M KStar -c KStar.cfg genStructDEE System.cfg GenStruct.cfg 1 MET GLY ASP ARG FCL unMinE: minE: bestE: MET GLY ASP MET FCL unMinE: minE: bestE: MET GLY ASP ARG FCL unMinE: minE: bestE: MET GLY SER ARG FCL unMinE: minE: bestE: MET GLY SER ARG FCL unMinE: minE: bestE: genStructDEE input structure rotamer library energy function struct generation parameters energy minimization (MinDEE, BD, B RDEE ) 1 MET GLY SER ARG FCL unMinE: minE: bestE: MET GLY SER ARG FCL unMinE: minE: bestE: MET GLY ASP ARG FCL unMinE: minE: bestE: rank

18 Ensemble-based: Protein-ligand binding mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi KSMaster System.cfg MutSearch.cfg bound structure rotamer library energy function mutation search parameters energy minimization (MinDEE, BD, B RDEE ) KSMaster doSinglePartFn E+24 ILE TRP ILE ALA ALA ILE E+24 TRP ASP ILE GLY ALA ILE E+24 ILE THR ILE PHE ALA ILE E+24 VAL THR ILE PHE ALA ILE E+24 ILE THR ILE TYR ALA ILE K*

19 Residue entropy mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi doResEntropy System.cfg ResEntropy.cfg input structure rotamer library energy function mutation search parameters doResEntropy res ID entropy AA probabilities # prox res

20 Some important parameters KStar.cfg: hElect true hVDW false hSteric false distDepDielect true dielectConst 6.0 vdwMult 0.95 doDihedE true doSolvationE true solvScale 0.8 stericThresh 0.4 softStericThresh 1.5 rotFile LovellRotamer.dat grotFile GenericRotamers.dat volFile AAVolumes.dat energy function steric filter rotamer libraries volume filter mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg

21 Some important parameters System.cfg: pdbName 1amuFH.pdb numInAS 4 residueMap pdbLigNum 566 ligAA false numCofRes 1 cofMap 567 input pdb design site ligand cofactor mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg

22 Some important parameters mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg DEE.cfg (partial) : doDACS true distrDACS false initDepth 2 subDepth 1 diffFact 6 doMinimize false minimizeBB false doBackrubs false backrubFile none useEref true ligPresent false ligType none resAllowed0 gly ala val leu ile tyr phe trp met … resAllowed3 gly ala val leu ile tyr phe trp met resumeSearch false resumeFilename runInfo.out.partial DACS minimization reference energies allowed mutations resuming ligand in search

23 Some important parameters mpirun -machinefile./machines -np 5 java -Xmx1024M KStar mpi KSMaster System.cfg MutSearch.cfg MutSearch.cfg (partial) : mutFileName 1amuFCL_2MUT.mut numMutations 2 targetVolume volumeWindow doMinimize false minimizeBB false doBackrubs false backrubFile none epsilon 0.03 gamma 0.01 repeatSearch true useUnboundStruct false unboundPdbName none resAllowed0 gly ala val leu ile tyr phe trp met resumeSearch false resumeFilename 1amuFCL_MutSearch.partial volume filter/ candidate mutants minimization inter-mutation allowed mutations resuming (1-ε) accuracy at most 1 repeat unbound struct

24 General citation: K* and MinDEE: BD: B RDEE : Citing OSPREY DACS: Original K* publication:

25 OSPREY is open source!!!

26 Acknowledgements Bruce Donald Ryan Lilien Faisal Reza Kyle Roberts Daniel Keedy Pablo Gainza Donald Lab Funding : NIH NIH

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