Minimize protein-covalent ligand complex with AMBER: Difference between revisions
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Save the | Save the protonated molecule in pdb format and rename the atoms: | ||
cat 94F.full_mod_num.pdb | cat 94F.full_mod_num.pdb | ||
Revision as of 19:47, 3 January 2019
This is for ligands that modify a specific residue.
(1) Make a directory:
mkdir coval_min cd coval_min/
(2) Download pdb file from the web:
wget https://files.rcsb.org/view/5YY1.pdb
(3) Manually create 3 files using your favorate text editor: a covalent ligand, a co-facotor and a receptor file.
(3.1) for the receptor, rec.pdb:
Change the covalent cysteine to reduce name CYM.
Here is a modified cystiene residue (this is without a charge and without a hydrogen):
cat CYM.prep
0 0 2
CYSTEINE without h and without charge for covalent
CYM INT 0
CORR OMIT DU BEG
0.00000
1 DUMM DU M 0 -1 -2 0.000 0.000 0.000 0.00000
2 DUMM DU M 1 0 -1 1.449 0.000 0.000 0.00000
3 DUMM DU M 2 1 0 1.522 111.100 0.000 0.00000
4 N N M 3 2 1 1.335 116.600 180.000 -0.41570
5 H H E 4 3 2 1.010 119.800 0.000 0.27190
6 CA CX M 4 3 2 1.449 121.900 180.000 0.02130
7 HA H1 E 6 4 3 1.090 109.500 300.000 0.11240
8 CB 2C 3 6 4 3 1.525 111.100 60.000 -0.12310
9 HB2 H1 E 8 6 4 1.090 109.500 300.000 0.11120
10 HB3 H1 E 8 6 4 1.090 109.500 60.000 0.11120
11 SG SH E 8 6 4 1.810 116.000 180.000 -0.23580
12 C C M 6 4 3 1.522 111.100 180.000 0.59730
13 O O E 12 6 4 1.229 120.500 0.000 -0.56790
IMPROPER
-M CA N H
CA +M C O
DONE
STOP
Here is a frcmod file with need parameters:
cat thioe.frcmod
Nir and trent got the parms from gaff and change the names, for thio-ether MASS BOND c3-SH 225.8 1.8210 SOURCE1 358 0.0075 C -SH 225.8 1.8210 SOURCE1 358 0.0075 ANGLE 2C-SH-c3 60.63 99.92 SOURCE3 14 2.0723 CT-SH-c3 60.63 99.92 SOURCE3 14 2.0723 c3-c3-SH 61.10 112.69 SOURCE3 24 2.1842 hc-c3-SH 42.51 108.76 SOURCE2 3 1.6891 SH-c3-h1 42.51 108.76 SOURCE2 3 1.6891 DIHE X -c3-SH-X 3 1.000 0.000 3.000 JCC,7,(1986),230 IMPROPER NONBON
These parameter values were taken from the gaff force field (/nfs/soft/amber/amber14/dat/leap/parm/gaff.dat).
(3.2) for a covalent ligand, lig.pdb:
keep the sidechain of the mofifed cystien:
cat 94F_bkup.pdb
ATOM 89 CA CYS A 12 29.215 -1.013 17.747 1.00 23.10 C ATOM 92 CB CYS A 12 30.264 -1.172 18.849 1.00 23.68 C ATOM 93 SG CYS A 12 29.632 -1.020 20.503 1.00 25.01 S ATOM 1385 C31 94F A 203 16.511 -4.125 24.817 1.00 32.17 C ATOM 1386 C30 94F A 203 15.606 -4.260 23.787 1.00 32.36 C ATOM 1387 C32 94F A 203 17.840 -3.910 24.531 1.00 31.54 C ATOM 1388 C29 94F A 203 16.037 -4.183 22.484 1.00 32.47 C ATOM 1389 C19 94F A 203 21.614 -2.199 22.881 1.00 29.12 C ATOM 1390 C5 94F A 203 23.964 -5.464 22.540 1.00 29.57 C ATOM 1391 C18 94F A 203 22.453 -3.293 22.771 1.00 29.13 C ATOM 1392 C23 94F A 203 18.284 -3.829 23.223 1.00 31.43 C ATOM 1393 C22 94F A 203 19.692 -3.612 23.019 1.00 29.79 C ATOM 1394 C24 94F A 203 17.372 -3.972 22.203 1.00 32.05 C ATOM 1395 C3 94F A 203 21.900 -4.565 22.770 1.00 29.39 C ATOM 1396 C2 94F A 203 20.533 -4.693 22.895 1.00 29.45 C ATOM 1397 C20 94F A 203 20.247 -2.347 23.012 1.00 29.51 C ATOM 1398 C7 94F A 203 23.836 -3.189 22.644 1.00 28.94 C ATOM 1399 C14 94F A 203 29.536 0.583 20.690 1.00 25.47 C ATOM 1400 C13 94F A 203 28.376 1.143 21.474 1.00 26.40 C ATOM 1401 C12 94F A 203 27.093 0.850 20.795 1.00 26.10 C ATOM 1402 C9 94F A 203 23.979 -0.953 21.731 1.00 28.62 C ATOM 1403 C17 94F A 203 25.969 -2.149 22.595 1.00 29.17 C ATOM 1404 C10 94F A 203 25.024 -0.390 20.794 1.00 28.12 C ATOM 1405 C16 94F A 203 26.678 -0.809 22.586 1.00 28.22 C ATOM 1406 C25 94F A 203 17.826 -3.897 20.794 1.00 32.91 C ATOM 1407 N4 94F A 203 22.652 -5.665 22.653 1.00 29.29 N ATOM 1408 N6 94F A 203 24.595 -4.289 22.534 1.00 29.70 N ATOM 1409 N8 94F A 203 24.523 -1.948 22.642 1.00 29.33 N ATOM 1410 N11 94F A 203 26.238 0.005 21.476 1.00 27.18 N ATOM 1411 O15 94F A 203 26.847 1.362 19.713 1.00 25.34 O ATOM 1412 F1 94F A 203 19.995 -5.935 22.878 1.00 29.69 F ATOM 1413 F26 94F A 203 16.791 -3.770 19.931 1.00 34.77 F ATOM 1414 F27 94F A 203 18.674 -2.862 20.538 1.00 31.92 F ATOM 1415 F28 94F A 203 18.495 -5.026 20.445 1.00 33.49 F ATOM 1416 CL 94F A 203 19.224 -0.960 23.165 1.00 29.22 CL
change and make the numbering and naming consistent:
cat 94F.pdb
ATOM 1382 CA LIG A 203 29.215 -1.013 17.747 1.00 23.10 C ATOM 1383 CB LIG A 203 30.264 -1.172 18.849 1.00 23.68 C ATOM 1384 SG LIG A 203 29.632 -1.020 20.503 1.00 25.01 S ATOM 1385 C31 LIG A 203 16.511 -4.125 24.817 1.00 32.17 C ATOM 1386 C30 LIG A 203 15.606 -4.260 23.787 1.00 32.36 C ATOM 1387 C32 LIG A 203 17.840 -3.910 24.531 1.00 31.54 C ATOM 1388 C29 LIG A 203 16.037 -4.183 22.484 1.00 32.47 C ATOM 1389 C19 LIG A 203 21.614 -2.199 22.881 1.00 29.12 C ATOM 1390 C5 LIG A 203 23.964 -5.464 22.540 1.00 29.57 C ATOM 1391 C18 LIG A 203 22.453 -3.293 22.771 1.00 29.13 C ATOM 1392 C23 LIG A 203 18.284 -3.829 23.223 1.00 31.43 C ATOM 1393 C22 LIG A 203 19.692 -3.612 23.019 1.00 29.79 C ATOM 1394 C24 LIG A 203 17.372 -3.972 22.203 1.00 32.05 C ATOM 1395 C3 LIG A 203 21.900 -4.565 22.770 1.00 29.39 C ATOM 1396 C2 LIG A 203 20.533 -4.693 22.895 1.00 29.45 C ATOM 1397 C20 LIG A 203 20.247 -2.347 23.012 1.00 29.51 C ATOM 1398 C7 LIG A 203 23.836 -3.189 22.644 1.00 28.94 C ATOM 1399 C14 LIG A 203 29.536 0.583 20.690 1.00 25.47 C ATOM 1400 C13 LIG A 203 28.376 1.143 21.474 1.00 26.40 C ATOM 1401 C12 LIG A 203 27.093 0.850 20.795 1.00 26.10 C ATOM 1402 C9 LIG A 203 23.979 -0.953 21.731 1.00 28.62 C ATOM 1403 C17 LIG A 203 25.969 -2.149 22.595 1.00 29.17 C ATOM 1404 C10 LIG A 203 25.024 -0.390 20.794 1.00 28.12 C ATOM 1405 C16 LIG A 203 26.678 -0.809 22.586 1.00 28.22 C ATOM 1406 C25 LIG A 203 17.826 -3.897 20.794 1.00 32.91 C ATOM 1407 N4 LIG A 203 22.652 -5.665 22.653 1.00 29.29 N ATOM 1408 N6 LIG A 203 24.595 -4.289 22.534 1.00 29.70 N ATOM 1409 N8 LIG A 203 24.523 -1.948 22.642 1.00 29.33 N ATOM 1410 N11 LIG A 203 26.238 0.005 21.476 1.00 27.18 N ATOM 1411 O15 LIG A 203 26.847 1.362 19.713 1.00 25.34 O ATOM 1412 F1 LIG A 203 19.995 -5.935 22.878 1.00 29.69 F ATOM 1413 F26 LIG A 203 16.791 -3.770 19.931 1.00 34.77 F ATOM 1414 F27 LIG A 203 18.674 -2.862 20.538 1.00 31.92 F ATOM 1415 F28 LIG A 203 18.495 -5.026 20.445 1.00 33.49 F ATOM 1416 CL LIG A 203 19.224 -0.960 23.165 1.00 29.22 CL
Uses chimera to add hydrogens:
Save the protonated molecule in pdb format and rename the atoms:
cat 94F.full_mod_num.pdb
HETATM 1 C01 LIG A 1 29.215 -1.013 17.747 1.00 0.00 C HETATM 2 C02 LIG A 1 30.264 -1.172 18.849 1.00 0.00 C HETATM 3 S03 LIG A 1 29.632 -1.020 20.503 1.00 0.00 S HETATM 4 C04 LIG A 1 16.511 -4.125 24.817 1.00 0.00 C HETATM 5 C05 LIG A 1 15.606 -4.260 23.787 1.00 0.00 C HETATM 6 C06 LIG A 1 17.840 -3.910 24.531 1.00 0.00 C HETATM 7 C07 LIG A 1 16.037 -4.183 22.484 1.00 0.00 C HETATM 8 C08 LIG A 1 21.614 -2.199 22.881 1.00 0.00 C HETATM 9 C09 LIG A 1 23.964 -5.464 22.540 1.00 0.00 C HETATM 10 C10 LIG A 1 22.453 -3.293 22.771 1.00 0.00 C HETATM 11 C11 LIG A 1 18.284 -3.829 23.223 1.00 0.00 C HETATM 12 C12 LIG A 1 19.692 -3.612 23.019 1.00 0.00 C HETATM 13 C13 LIG A 1 17.372 -3.972 22.203 1.00 0.00 C HETATM 14 C14 LIG A 1 21.900 -4.565 22.770 1.00 0.00 C HETATM 15 C15 LIG A 1 20.533 -4.693 22.895 1.00 0.00 C HETATM 16 C16 LIG A 1 20.247 -2.347 23.012 1.00 0.00 C HETATM 17 C17 LIG A 1 23.836 -3.189 22.644 1.00 0.00 C HETATM 18 C18 LIG A 1 29.536 0.583 20.690 1.00 0.00 C HETATM 19 C19 LIG A 1 28.376 1.143 21.474 1.00 0.00 C HETATM 20 C20 LIG A 1 27.093 0.850 20.795 1.00 0.00 C HETATM 21 C21 LIG A 1 23.979 -0.953 21.731 1.00 0.00 C HETATM 22 C22 LIG A 1 25.969 -2.149 22.595 1.00 0.00 C HETATM 23 C23 LIG A 1 25.024 -0.390 20.794 1.00 0.00 C HETATM 24 C24 LIG A 1 26.678 -0.809 22.586 1.00 0.00 C HETATM 25 C25 LIG A 1 17.826 -3.897 20.794 1.00 0.00 C HETATM 26 N26 LIG A 1 22.652 -5.665 22.653 1.00 0.00 N HETATM 27 N27 LIG A 1 24.595 -4.289 22.534 1.00 0.00 N HETATM 28 N28 LIG A 1 24.523 -1.948 22.642 1.00 0.00 N HETATM 29 N29 LIG A 1 26.238 0.005 21.476 1.00 0.00 N HETATM 30 O30 LIG A 1 26.847 1.362 19.713 1.00 0.00 O HETATM 31 F31 LIG A 1 19.995 -5.935 22.878 1.00 0.00 F HETATM 32 F32 LIG A 1 16.791 -3.770 19.931 1.00 0.00 F HETATM 33 F33 LIG A 1 18.674 -2.862 20.538 1.00 0.00 F HETATM 34 F34 LIG A 1 18.495 -5.026 20.445 1.00 0.00 F HETATM 35 CL LIG A 1 19.224 -0.960 23.165 1.00 0.00 Cl HETATM 36 H36 LIG A 1 31.026 -0.406 18.705 1.00 0.00 H HETATM 37 H37 LIG A 1 30.732 -2.151 18.745 1.00 0.00 H HETATM 38 H38 LIG A 1 16.180 -4.188 25.843 1.00 0.00 H HETATM 39 H39 LIG A 1 14.561 -4.426 24.003 1.00 0.00 H HETATM 40 H40 LIG A 1 18.547 -3.803 25.340 1.00 0.00 H HETATM 41 H41 LIG A 1 15.328 -4.288 21.676 1.00 0.00 H HETATM 42 H42 LIG A 1 22.038 -1.206 22.864 1.00 0.00 H HETATM 43 H43 LIG A 1 24.581 -6.345 22.443 1.00 0.00 H HETATM 44 H44 LIG A 1 29.494 1.022 19.693 1.00 0.00 H HETATM 45 H45 LIG A 1 30.457 0.921 21.166 1.00 0.00 H HETATM 46 H46 LIG A 1 28.366 0.694 22.467 1.00 0.00 H HETATM 47 H47 LIG A 1 28.494 2.222 21.569 1.00 0.00 H HETATM 48 H48 LIG A 1 23.559 -0.136 22.317 1.00 0.00 H HETATM 49 H49 LIG A 1 23.184 -1.410 21.141 1.00 0.00 H HETATM 50 H50 LIG A 1 26.283 -2.718 23.470 1.00 0.00 H HETATM 51 H51 LIG A 1 26.228 -2.702 21.692 1.00 0.00 H HETATM 52 H52 LIG A 1 25.273 -1.150 20.054 1.00 0.00 H HETATM 53 H53 LIG A 1 24.608 0.478 20.282 1.00 0.00 H HETATM 54 H54 LIG A 1 27.752 -0.975 22.502 1.00 0.00 H HETATM 55 H55 LIG A 1 26.468 -0.286 23.519 1.00 0.00 H HETATM 56 H56 LIG A 1 29.692 -1.121 16.773 1.00 0.00 H HETATM 57 H57 LIG A 1 28.758 -0.026 17.820 1.00 0.00 H HETATM 58 H58 LIG A 1 28.448 -1.778 17.863 1.00 0.00 H CONECT 23 21 29 52 53 CONECT 20 19 29 30 CONECT 19 18 20 46 47 CONECT 18 3 19 44 45 CONECT 24 22 29 54 55 CONECT 22 24 28 50 51 CONECT 10 8 14 17 CONECT 8 10 16 42 CONECT 15 12 14 31 CONECT 16 8 12 35 CONECT 12 11 15 16 CONECT 11 6 12 13 CONECT 13 7 11 25 CONECT 25 13 32 33 34 CONECT 7 5 13 41 CONECT 14 10 15 26 CONECT 5 7 4 39 CONECT 4 6 5 38 CONECT 6 4 11 40 CONECT 9 26 27 43 CONECT 17 10 27 28 CONECT 21 23 28 48 49 CONECT 1 2 57 56 58 CONECT 2 1 3 36 37 CONECT 35 16 CONECT 31 15 CONECT 32 25 CONECT 33 25 CONECT 34 25 CONECT 52 23 CONECT 53 23 CONECT 46 19 CONECT 47 19 CONECT 44 18 CONECT 45 18 CONECT 54 24 CONECT 55 24 CONECT 50 22 CONECT 51 22 CONECT 42 8 CONECT 41 7 CONECT 39 5 CONECT 38 4 CONECT 40 6 CONECT 43 9 CONECT 48 21 CONECT 49 21 CONECT 56 1 CONECT 57 1 CONECT 58 1 CONECT 36 2 CONECT 37 2 CONECT 29 20 23 24 CONECT 26 9 14 CONECT 27 9 17 CONECT 28 17 21 22 CONECT 30 20 CONECT 3 2 18 END
run the following script:
cat run.002.ligprep.antechamber.csh
#! /bin/tcsh set workdir = `pwd` cd $workdir setenv AMBERHOME /nfs/soft/amber/amber14 rm lig; mkdir lig; cd lig cp $workdir/94F.full_mod_num.pdb lig.pdb $AMBERHOME/bin/antechamber -i lig.pdb -fi pdb -o lig.ante.mol2 -fo mol2 $AMBERHOME/bin/antechamber -i lig.ante.mol2 -fi mol2 -o lig.ante.charge.mol2 -fo mol2 -c bcc -at sybyl -nc 0 $AMBERHOME/bin/antechamber -i lig.ante.mol2 -fi mol2 -o lig.ante.pdb -fo pdb $AMBERHOME/bin/antechamber -i lig.ante.charge.mol2 -fi mol2 -o lig.ante.charge.prep -fo prepi $AMBERHOME/bin/parmchk -i lig.ante.charge.prep -f prepi -o lig.ante.charge.frcmod
modify the prep file to remove the cysteine side chain. Also add partial charge to covalent carbon to make the Cysteine (CYM) + covalent ligand an integer.
diff lig/lig.ante.charge.prep lig/lig.ante.charge.mod.prep
11,19c11 < 4 C01 c3 M 3 2 1 1.540 111.208 -180.000 -0.104100 < 5 H56 hc E 4 3 2 1.090 115.954 83.673 0.047367 < 6 H57 hc E 4 3 2 1.090 65.214 -175.770 0.047367 < 7 H58 hc E 4 3 2 1.089 45.251 -8.622 0.047367 < 8 C02 c3 M 4 3 2 1.530 133.294 -81.790 -0.002300 < 9 H36 h1 E 8 4 3 1.090 108.130 -134.600 0.074200 < 10 H37 h1 E 8 4 3 1.090 108.604 107.772 0.074200 < 11 S03 ss M 8 4 3 1.777 114.690 -13.854 -0.332200 < 12 C18 c3 M 11 8 4 1.617 102.332 -80.293 -0.008300 --- > 12 C18 c3 M 3 2 1 1.617 102.332 -80.293 -0.037200
(3.3) for a co-factory (gdp), gdp.pdb:
Add hydrogens to gdp is chimera.
build the prep and frcmod files with antechamber:
cat run.002.ligprep.antechamber_gdp.csh
#! /bin/tcsh set workdir = `pwd` cd $workdir setenv AMBERHOME /nfs/soft/amber/amber14 rm lig2; mkdir lig2; cd lig2 #cp $workdir/xtal-lig.pdb lig.pdb #cp $workdir/33443.pdb lig.pdb cp $workdir/gdp_h.pdb lig.pdb #sed -i 's/<0> /LIG/g' lig1.mol2 $AMBERHOME/bin/antechamber -i lig.pdb -fi pdb -o lig.ante.mol2 -fo mol2 $AMBERHOME/bin/antechamber -i lig.ante.mol2 -fi mol2 -o lig.ante.charge.mol2 -fo mol2 -c bcc -at sybyl -nc -3 $AMBERHOME/bin/antechamber -i lig.ante.mol2 -fi mol2 -o lig.ante.pdb -fo pdb $AMBERHOME/bin/antechamber -i lig.ante.charge.mol2 -fi mol2 -o lig.ante.charge.prep -fo prepi $AMBERHOME/bin/parmchk -i lig.ante.charge.prep -f prepi -o lig.ante.charge.frcmod
Here is the tleap input file:
cat tleap.in | awk '{print " "$0}'
set default PBradii mbondi2
# load the protein force field
source leaprc.ff12SB
# load in GAFF
source leaprc.gaff
# ions
loadamberparams /nfs/soft/amber/amber14/dat/leap/parm/frcmod.ionsjc_tip3p
loadamberparams /nfs/soft/amber/amber14/dat/leap/parm/frcmod.ionslrcm_hfe_tip3p
# load ligand and covalent parameters.
loadamberparams lig/lig.ante.charge.frcmod
loadamberparams lig2/lig.ante.charge.frcmod
loadamberparams thioe.frcmod
loadamberprep lig/lig.ante.charge.mod.prep
loadamberprep lig2/lig.ante.charge.prep
loadamberprep CYM.prep
# load pdb file
REC = loadpdb rec.pdb
LIG = loadpdb 94F.full_mod_num.pdb
COF = loadpdb gdp.pdb
#complex
COM = combine {REC COF LIG}
# draw bond between CYN and LIG
#bondByDistance COM 2.0
bond COM.172.C18 COM.12.SG
#bond COM.330.C COM.331.N
#bond COM.331.C COM.332.N
#deleteBond COM.331.SG COM.331.C
#desc COM.331
#desc COM.331.SG
#desc COM.331.C
#desc COM.331.N
#desc COM.501
desc COM.172.C18
desc COM.12.SG
saveamberparm COM com.leap.prm7 com.leap.rst7
quit
Here is the command to run leap:
$AMBERHOME/bin/tleap -s -f tleap.in > ! tleap.out
Here is the command to submit the miminization to the queue:
cat run.004.pmemd_cuda_min.csh | awk '{print " "$0}'
#setenv AMBERHOME /nfs/soft/amber/amber14 setenv AMBERHOME /nfs/soft/amber/amber14 setenv LD_LIBRARY_PATH "" #setenv LD_LIBRARY_PATH "/usr/local/cuda-6.0/lib64/:$LD_LIBRARY_PATH" setenv LD_LIBRARY_PATH "/nfs/soft/cuda-6.5/lib64/:\$LD_LIBRARY_PATH" cat << EOF1 > ! 01mi.in 01mi.in: minimization with GB &cntrl imin = 1, maxcyc = 10000, ncyc = 500, ntmin = 1, igb=1, ntx = 1, ntc = 1, ntf = 1, ntb = 0, ntp = 0, ntwx = 1000, ntwe = 0, ntpr = 1000, cut = 999.9, ntr = 1, restraintmask = '!@H=', restraint_wt = 0.1, / EOF1 #$AMBERHOME/bin/pmemd.cuda -O -i 01mi.in -o 01mi.out -p com.leap.prm7 -c com.leap.rst7 -ref com.leap.rst7 -x 01mi.mdcrd -inf 01mi.info -r 01mi.rst7 #$AMBERHOME/bin/sander -O -i 01mi.in -o 01mi.out -p com.leap.prm7 -c com.leap.rst7 -ref com.leap.rst7 -x 01mi.mdcrd -inf 01mi.info -r 01mi.rst7 set pwd = `pwd` #cd $pwd cat << EOF > ! qsub.sander.csh #\$ -S /bin/csh #\$ -cwd #\$ -q gpu.q #\$ -o stdout #\$ -e stderr cd $pwd $AMBERHOME/bin/pmemd.cuda -O -i 01mi.in -o 01mi.out -p com.leap.prm7 -c com.leap.rst7 -ref com.leap.rst7 -x 01mi.mdcrd -inf 01mi.info -r 01mi.rst7 EOF qsub qsub.sander.csh
Visualize the minimized coordinates with Chimera or VMD, you can first convert the files to pdb format with the following commands:
$AMBERHOME/bin/ambpdb -p com.leap.prm7 < 01mi.rst7 > 01mi.pdb
$AMBERHOME/bin/ambpdb -p com.leap.prm7 < com.leap.rst7 > com.leap.pdb