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OSPREYTutorial
Ivelin Georgiev
Donald LabDuke University
Installation
Setup
Running OSPREY
Installation
MPICH2mpiJavaJava
32-bit 64-bit
√ may requirespecial instructions
Setup
Input Structure
Rotamer Library
Energy Function
Compute Nodes
Compute Nodes
mpirun java OSPREY
Select MPI nodes:linux1linux2linux3linux4linux5
mpdboot
mpdboot -n 5 -f mpd.hosts
linux1linux1linux1linux2linux3linux3
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg
Select job-specific nodes:
Input Structure
missingatoms
model delete
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
possibleover-constraint
possibleunder-constraint
Input Structure
addinghydrogens
generalcompounds
proteins
recommended:MolProbity
recommended:Accelrys DS Visualizer
Check: protonation states missing protons
Input Structure
Hisresidues
HIP HIE HID
Input Structure
stericshell
• close to design site• significant speedup
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)
Input Structure
Check and double-check!!!
Rotamer Library
rotamers
generalcompounds
proteins
Richardsons’Penultimate
TYR 2 4N CA CB CGCA CB CG CD162 90-177 80-65 -85-65 -30
TYR 2 5N CA CB CGCA CB CG CD162 90-177 80-65 -85-65 -30-65 -45
FCL 2 4N CA CB CGCA CB CG CD162 90-177 80-65 -85-65 -30one rotamer
1 2
name
# dihed# rot
Energy Function
parm96a.dat all_amino94X.in all_nuc94_and_gr.in
• atom types• dihedral parameters• vdW parameters
add params fornew atom types
antechamber
• amino acids • partial charges• connectivity
typicallyno changes
can modifypartial charges
• general compounds • partial charges• connectivity
add params fornew compounds
antechamber
user control: distance-dependent dielectric, dielectric value, vdW radii scaling, solvation energy scaling, dihedral energies switch
Running OSPREY
Ensemble-based
Residue entropy
GMEC-based
GMEC-based
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg
input structurerotamer libraryenergy function mutation search
parameters
energy minimization(MinDEE, BD, BRDEE)
DACS
doDEE
1 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.752 MET GLY ASP MET FCL 6 0 2 6 3 unMinE: -271.96 minE: -271.96 bestE: -273.753 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -271.78 minE: -271.78 bestE: -273.751 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.502 MET GLY SER ARG FCL 6 3 1 18 2 unMinE: -276.42 minE: -276.42 bestE: -276.50
GMEC-based
java -Xmx1024M KStar -c KStar.cfg genStructDEE System.cfg GenStruct.cfg
1 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.752 MET GLY ASP MET FCL 6 0 2 6 3 unMinE: -271.96 minE: -271.96 bestE: -273.753 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -271.78 minE: -271.78 bestE: -273.751 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.502 MET GLY SER ARG FCL 6 3 1 18 2 unMinE: -276.42 minE: -276.42 bestE: -276.50
genStructDEE
input structurerotamer libraryenergy function struct generation
parameters
energy minimization(MinDEE, BD, BRDEE)
1 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.502 MET GLY SER ARG FCL 6 3 1 18 2 unMinE: -276.42 minE: -276.42 bestE: -276.503 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.75
rank
Ensemble-based: Protein-ligand bindingmpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi KSMaster System.cfg MutSearch.cfg
bound structurerotamer libraryenergy function mutation search
parameters
energy minimization(MinDEE, BD, BRDEE)KSMaster
doSinglePartFn
1 4.25E+24 ILE TRP ILE ALA ALA ILE2 3.12E+24 TRP ASP ILE GLY ALA ILE3 2.18E+24 ILE THR ILE PHE ALA ILE4 1.45E+24 VAL THR ILE PHE ALA ILE5 1.41E+24 ILE THR ILE TYR ALA ILE
K*
Residue entropy
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi doResEntropy System.cfg ResEntropy.cfg
input structurerotamer libraryenergy function mutation search
parameters
doResEntropy
257 2.33 0.2 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.2 0.0 0.1 18 481 2.29 0.2 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.2 0.0 0.0 0.0 0.1 0.0 0.1 15 32 2.29 0.3 0.0 0.1 0.1 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 23 26 2.28 0.2 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.2 0.0 0.0 0.1 0.1 0.0 29 163 2.26 0.3 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.1 22
res IDentropy
AA probabilities # prox res
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
energyfunction
steric filter
rotamer libraries
volume filter
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg
Some important parameters
System.cfg:
pdbName 1amuFH.pdb
numInAS 4
residueMap 239 278 299 301
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
Some important parametersmpirun -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
Some important parametersmpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi KSMaster System.cfg MutSearch.cfg
MutSearch.cfg (partial):mutFileName 1amuFCL_2MUT.mut
numMutations 2
targetVolume 620.0
volumeWindow 100000000.0
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
General citation:
K* and MinDEE:
BD:
BRDEE:
CitingOSPREY
DACS:
Original K* publication:
OSPREY is open source!!!
Acknowledgements
Bruce DonaldRyan Lilien
Faisal RezaKyle RobertsDaniel KeedyPablo Gainza
Donald Lab
FundingFunding: : • NIHNIH