osprey tutorial ivelin georgiev donald lab duke university

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


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


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

…


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


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

osprey tutorial ivelin georgiev donald lab duke university

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