Transcript OSPREY Tutorial Ivelin Georgiev Donald Lab Duke University Installation Setup Running OSPREY Installation Java mpiJava 32-bit MPICH2 64-bit may require special instructions Setup Compute Nodes Input Structure Rotamer Library Energy Function.

OSPREY
Tutorial
Ivelin Georgiev
Donald Lab
Duke University
Installation
Setup
Running OSPREY
Installation
Java
mpiJava
32-bit
MPICH2
64-bit
may require
special instructions
Setup
Compute Nodes
Input Structure
Rotamer Library
Energy Function
Compute Nodes
Select MPI nodes:
linux1
linux2
linux3
linux4
linux5
mpdboot
mpdboot -n 5 -f mpd.hosts
Select job-specific nodes:
linux1
linux1
linux1
linux2
linux3
linux3
mpirun
java
OSPREY
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg
Input Structure
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
missing
atoms
KiNG
model
delete
possible
over-constraint
possible
under-constraint
Input Structure
adding
hydrogens
proteins
general
compounds
recommended:
MolProbity
recommended:
Accelrys DS Visualizer
Check: protonation states
missing protons
Input Structure
His
residues
HIP
HIE
HID
Input Structure
steric
shell
• 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
Richardsons’
Penultimate
proteins
general
compounds
# dihed
TYR 2 4
N CA CB CG
CA CB CG CD1
62 90
-177 80
-65 -85
-65 -30
TYR 2 5
N CA CB CG
CA CB CG CD1
62 90
-177 80
-65 -85
-65 -30
-65 -45
name
1
one rotamer
FCL 2 4
N CA CB CG
CA CB CG CD1
2
62 90
-177 80
-65 -85
-65 -30
# rot
Energy Function
parm96a.dat
• atom types
• dihedral parameters
• vdW parameters
add params for
new atom types
antechamber
all_amino94X.in
all_nuc94_and_gr.in
• amino acids
• partial charges
• connectivity
• general compounds
• partial charges
• connectivity
typically
no changes
can modify
partial charges
add params for
new compounds
antechamber
user control: distance-dependent dielectric, dielectric value,
vdW radii scaling, solvation energy scaling, dihedral energies switch
Running OSPREY
GMEC-based
Ensemble-based
Residue entropy
GMEC-based
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
doDEE
energy minimization
(MinDEE, BD, BRDEE)
DACS
1 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.75
2 MET GLY ASP MET FCL 6 0 2 6 3 unMinE: -271.96 minE: -271.96 bestE: -273.75
3 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -271.78 minE: -271.78 bestE: -273.75
1 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.50
2 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
input structure
rotamer library
energy function
struct generation
parameters
genStructDEE
energy minimization
(MinDEE, BD, BRDEE)
1 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.50
2 MET GLY SER ARG FCL 6 3 1 18 2 unMinE: -276.42 minE: -276.42 bestE: -276.50
3 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.75
rank
1 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -273.75 minE: -273.75 bestE: -273.75
2 MET GLY ASP MET FCL 6 0 2 6 3 unMinE: -271.96 minE: -271.96 bestE: -273.75
3 MET GLY ASP ARG FCL 6 0 2 18 3 unMinE: -271.78 minE: -271.78 bestE: -273.75
1 MET GLY SER ARG FCL 6 3 2 18 2 unMinE: -276.50 minE: -276.50 bestE: -276.50
2 MET GLY SER ARG FCL 6 3 1 18 2 unMinE: -276.42 minE: -276.42 bestE: -276.50
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
KSMaster
K*
energy minimization
(MinDEE, BD, BRDEE)
doSinglePartFn
1
2
3
4
5
4.25E+24
3.12E+24
2.18E+24
1.45E+24
1.41E+24
ILE TRP ILE ALA ALA ILE
TRP ASP ILE GLY ALA ILE
ILE THR ILE PHE ALA ILE
VAL THR ILE PHE ALA ILE
ILE THR ILE TYR ALA ILE
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
entropy
res ID
257
481
32
26
163
# prox res
AA probabilities
2.33
2.29
2.29
2.28
2.26
0.2
0.2
0.3
0.2
0.3
0.0
0.0
0.0
0.0
0.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.0
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
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.1
0.1
0.1
0.0
0.2
0.0
0.1
0.2
0.0
0.0
0.0
0.0
0.0
0.0
0.2
0.0
0.0
0.0
0.0
0.0
0.1
0.0
0.0
0.0
0.0
0.0
0.2
0.1
0.1
0.1
0.1
0.0
0.0
0.0
0.1
0.0
0.1
0.1
0.1
0.0
0.1
18
15
23
29
22
Some important parameters
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg
KStar.cfg:
hElect true
hVDW false
energy
function
hSteric false
distDepDielect true
dielectConst 6.0
vdwMult 0.95
doDihedE true
doSolvationE true
solvScale 0.8
steric filter
rotamer libraries
volume filter
stericThresh 0.4
softStericThresh 1.5
rotFile LovellRotamer.dat
grotFile GenericRotamers.dat
volFile AAVolumes.dat
Some important parameters
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi -c KStar.cfg doDEE System.cfg DEE.cfg
System.cfg:
input pdb
design site
ligand
cofactor
pdbName 1amuFH.pdb
numInAS 4
residueMap 239 278 299 301
pdbLigNum 566
ligAA false
numCofRes 1
cofMap 567
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
DACS
initDepth 2
subDepth 1
diffFact 6
doMinimize false
minimization
minimizeBB false
doBackrubs false
backrubFile none
reference energies
ligand in search
allowed mutations
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
resuming
resumeSearch false
resumeFilename runInfo.out.partial
Some important parameters
mpirun -machinefile ./machines -np 5 java -Xmx1024M KStar mpi KSMaster System.cfg MutSearch.cfg
MutSearch.cfg (partial):
mutFileName 1amuFCL_2MUT.mut
volume filter/
candidate mutants
numMutations 2
targetVolume 620.0
volumeWindow 100000000.0
doMinimize false
minimization
(1-ε) accuracy
inter-mutation
at most 1 repeat
unbound struct
allowed mutations
resuming
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
Citing
OSPREY
General citation:
K* and MinDEE:
BD:
BRDEE:
DACS:
Original K* publication:
OSPREY is open source!!!
Acknowledgements
Bruce Donald
Ryan Lilien
Funding:
• NIH
Faisal Reza
Kyle Roberts
Daniel Keedy
Pablo Gainza
Donald Lab