docking of 1gj7 (A18) into model1

model1.pdb uPA receptor model1
1gj7_lig.sdf 2D ligand sdf
1gj7_lig3d.sdf 3D ligand sdf prepared by CORINA
1gj7_lig_doc.sdf 10 best docking solutions ranked by GOLD
1gj7_lig_doc_sol1.sdf docking solution 1 (flipped)
1gj7_lig_doc_sol3.sdf docking solution 3 (best solution)
sdf
model1.sol1.protmin.restrain.in:
cntrl
maxcyc=500, imin=1, ntmin=1, ncyc=100, nsnb=20,
igb=0, ntb=0, dielc=80.0, ntpr=10,
ntr=1,
cut = 15.0
end
ewald
eedmeth=5,
end

program folder: /home/henricsn/combine2go/programs/

12.07.05

xleap.sh -gold -sdf 1gj7_lig_doc_sol1.sdf -n go1 -prot model1.pdb \
-pdb model1 -alt sol1 -notemp -min model1.sol1.protmin.restrain.in \
-noac -nopc -noleap -edit

solution3:
xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol3_dielc1 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol3_dielc1.min.pdb dielc=1.0 eedmeth=5

xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol3_dielc4 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol3_dielc4.min.pdb dielc=4.0 eedmeth=5

xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol3_dielc80 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol3_dielc80.min.pdb dielc=80.0 eedmeth=5

model1-1gj7-sol3-minpdb.tar

solution1
xleap.sh -gold -sdf 1gj7_lig_doc_sol1.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol1_dielc1 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol1_dielc1.min.pdb dielc=1.0 eedmeth=5

xleap.sh -gold -sdf 1gj7_lig_doc_sol1.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol1_dielc4 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol1_dielc4.min.pdb dielc=4.0 eedmeth=5

xleap.sh -gold -sdf 1gj7_lig_doc_sol1.sdf -n go1 -prot model1.pdb -pdb model1 -alt sol1_dielc80 -notemp -min model1.sol1.protmin.restrain.in -edit
./model1.sol1_dielc80.min.pdb dielc=80.0 eedmeth=5

model1-1gj7-sol1-minpdb.tar

xray structure complex 1gj7
xleap.sh -sdf A18.sdf -n A18 -prot 1gj7.192A.deprH57.modif.align.pdb -pdb 1gj7 -alt xray_dielc4 -notemp -min 1gj7.protmin.restrain.in -edit -lig 1gj7.prot.ligand.align.pdb

xray-1gj7-minpdb.tar

results

pymol - dock_sol1_sol3_dielc.pse
1gj7_lig_doc 1gj7_lig_doc.sdf 10 best docking solutions ranked by GOLD
model1 model1.pdb receptor model1
dock_sol1 1gj7_lig_doc_sol1.sdf docking solution 1 (flipped)
dock_sol3 1gj7_lig_doc_sol3.sdf docking solution 3 (best solution)
sol3_dielc1 model1.sol3_dielc1.min.pdb
sol3_dielc4 model1.sol3_dielc4.min.pdb
sol3_dielc80 model1.sol3_dielc80.min.pdb
sol3_dielc80 model1.sol1_dielc80.min.pdb
sol3_dielc4 model1.sol1_dielc4.min.pdb
sol3_dielc1 model1.sol1_dielc1.min.pdb
1gj7.prot.ligand xray-structure of ligand 1gj7
1gj7.align xray structure of receptor 1gj7
1gj7.xray_dielc4.min minimized xray structure of complex 1gj7-A, dielc=4.0, with crystallographic water
1gj7.xray_dielc1.min minimized xray structure of complex 1gj7-A, dielc=1.0, with crystallographic water
1gj7.xray_dielc80.min minimized xray structure of complex 1gj7-A, dielc=80.0, with crystallographic water

Choosing dielc=4 improves the minimization of the docked ligand very much. dielc=80 gives no better results. All
minimized docking solutions are showing distortions of the ring system next to the amidino group. This ring distortion
can not be found in the minimized xray structure with explicit crystallographic water molecules.

The sander output shows completly different energy values, eg. sol1:
dielc=1 energy=-1.2495E+03
dielc=4 energy=9.5266E+02
dielc=80 energy=1.5518E+03

Less than 400 minimization cycles seem to be enough for minimization of docked ligands.

13.07.05


b70-100_2.4.pdb water sites from cluster analysis with occ 70 %

xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n A18 -prot model1.pdb -pdb model1 -alt sol3_dielc4_wat70-100 -min model1.sol1.protmin.restrain.in -edit -wat b70-100_2.4.pdb -w

-- model1.sol3_dielc4_wat70-100.min.pdb
Also with some conserved water molecules the ring system is distorted.

20.07.05


for minimization of docking solutions:
first mimization script: minH.restrain.in

#hydrogens
#200 steps of minimization of hydrogens, distance-dependent dielectric in AMBER8
cntrl
maxcyc=200, imin=1, ntmin=1, ncyc=100, nsnb=20,
igb=0, ntb=0, dielc=4.0, ntpr=10,
ntr=1,restraint_wt=5000.0, restraintmask='!@H='
cut = 15.0
end
ewald
eedmeth=5,
end
END

second minimization script: docking.restrain.in
#template
#500 steps of minimization, distance-dependent dielectric in AMBER8
cntrl
maxcyc=300, imin=1, ntmin=1, ncyc=100, nsnb=20,
igb=0, ntb=0, dielc=4.0, ntpr=10,
ntr=1,
cut = 15.0
end
ewald
eedmeth=5,
end
restrain ligand atoms except H
0.0
FIND
* * M *
* * S *
* * B *
* * 3 *
* * 4 *
* * 5 *
* * 6 *
SEARCH
RES 256
END
restrain protein atoms except H, ligand, and wat
10.0
FIND
* CT * *
* C * *
* C* * *
SEARCH
RES 1 255
END
restrain protein atoms except H
10.0
FIND
* CA * *
* CB * *
* CC * *
* CK * *
* CM * *
* CN * *
* CQ * *
* CR * *
* CV * *
* CW * *
SEARCH
RES 1 255
END
restrain protein atoms except H
10.0
FIND
* N3 * *
* N * *
* N* * *
* N2 * *
* NA * *
* NB * *
* NC * *
SEARCH
RES 1 255
END
restrain protein atoms except H
10.0
FIND
* OH * *
* OS * *
* O * *
* O2 * *
* P * *
* S * *
* SH * *
SEARCH
RES 1 255
END
END


two-step minimization of docking solution 3 with hydrogens 70-100 %:
xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n A18 -prot model1.pdb -pdb model1 -alt sol3_dielc4_wat70-100_Hmin -min docking.restrain.in -edit -wat b70-100_2.4.pdb -w
= model1.sol3_dielc4_wat70-100_Hmin.min.pdb

21.07.05


two-step minimization of docking solution 3 w/o hydrogens:
1. 200 cycles 2. 500 cycles
xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n A18 -prot model1.pdb -pdb model1 -alt sol3_dielc4_H -min docking.restrain.in -notemp -noac -nopc -noleap
1. = model1.sol3_dielc4_H.minH.pdb
2. = model1.sol3_dielc4_H.min.pdb


two-step minimization of docking solution 3 with hydrogens 70-100 %:
1. 200 cycles 2. 500 cycles
xleap.sh -gold -sdf 1gj7_lig_doc_sol3.sdf -n A18 -prot model1.pdb -pdb model1 -alt sol3_dielc4_H_wat70 -min docking.restrain.in -notemp -w wat b70-100_2.4.pdb
1. all hydrogens (minH.restrain.in) - ./model1.sol3_dielc4_H_wat70.minH.pdb
2. all atoms (docking.restrain.in) - ./model1.sol3_dielc4_H_wat70.min.pdb

In sol3 there are no much differences between minimization in one step (w/o hydrogen
minimization separately) and two step (1. hydrogens, 2. all) minimization.
In sol1 (flipped) the differences are much stronger.


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update: 02.08.2005

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