Dear AMBER community,
I am utilizing the MM-PBSA method to compute the binding free energy
between a protein (residues 1-123) and its (degrader+VHL) (residues
124-286). The total simulation duration is 400 ns. Following an analysis of
the RMSD of backbone atoms relative to the X-ray structure, only the last
200 ns of the simulation were selected for MM-PBSA analysis. However, I
have encountered a significant standard deviation within my system. I am
seeking guidance on how to minimize this standard deviation. Below, I have
provided the input files for tleap, NVT production step, and the output of
MM-PBSA analysis:
source leaprc.protein.ff19SB
source leaprc.gaff
source leaprc.water.tip3p
IFJ = loadmol2 ligand_H.mol2 # mol2 for degrader
loadamberparams ligand_H.frcmod # force field for degrader
mol = loadpdb Ternary_VHL_renum.pdb # see the attach
savepdb mol Ternary_VHL_dry.pdb
saveamberparm mol Ternary_VHL_dry.prmtop Ternary_VHL_dry.inpcrd
solvatebox mol TIP3PBOX 18
addions mol K+ 0
addions mol Cl- 0 # 5 anions were added
savepdb mol Ternary_VHL_solv.pdb
saveamberparm mol Ternary_VHL_solv.prmtop Ternary_VHL_solv.inpcrd
quit
=============================================
NVT production 400 ns
&cntrl
imin=0, irest=0,
nstlim=200000000, dt=0.002, ntx=1,
ntpr=50000, ntwx=50000, ntwr=50000,
cut=12, ntb=1,
ntc=2, ntf=2,
ntt=3, gamma_ln=2.0,
tempi=300.0, temp0=300.0,
ioutfm=1, ntwv=-1, ig=-1, iwrap=1
&end
&wt
type='END'
&end
====================================
| Run on Wed Mar 6 12:32:41 2024
|
|Input file:
|--------------------------------------------------------------
|Input file for running PB and GB
|&general
| startframe=2000, endframe=4000, keep_files=2,
|/
|&gb
| igb=2, saltcon=0.100,
|/
|&pb
| istrng=0.100,
|/
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|--------------------------------------------------------------
|MMPBSA.py Version=14.0
|Solvated complex topology file: Ternary_VHL_solv.prmtop
|Complex topology file: Ternary_VHL_dry.prmtop
|Receptor topology file: Degrader_VHL_dry.prmtop
|Ligand topology file: SMARCA2_dry.prmtop
|Initial mdcrd(s): Ternary_VHL_solv_nvt_prod.netcdf
|
|Receptor mask: ":124-286"
|Ligand mask: ":1-123"
|
|Calculations performed using 2001.0 complex frames.
|Poisson Boltzmann calculations performed using internal PBSA solver in
mmpbsa_py_energy
|
|Generalized Born ESURF calculated using 'LCPO' surface areas
|
|All units are reported in kcal/mole.
-------------------------------------------------------------------------------
-------------------------------------------------------------------------------
GENERALIZED BORN:
WARNING: INCONSISTENCIES EXIST WITHIN INTERNAL POTENTIAL
TERMS. THE VALIDITY OF THESE RESULTS ARE HIGHLY QUESTIONABLE
Complex:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 943.6271 26.7114
0.5971
ANGLE 2550.9637 39.6714
0.8869
DIHED 1735.8770 22.1045
0.4941
VDWAALS -2313.3056 27.5916
0.6168
EEL -19193.5169 134.4839
3.0064
1-4 VDW 1074.4028 13.9567
0.3120
1-4 EEL 8444.6983 46.6150
1.0421
EGB -3985.8926 120.1555
2.6861
ESURF 116.0075 3.0462
0.0681
G gas -6757.2536 141.2106
3.1568
G solv -3869.8851 118.4075
2.6470
TOTAL -10627.1387 54.1755
1.2111
Receptor:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 555.9580 20.4648
0.4575
ANGLE 1505.2828 30.5134
0.6821
DIHED 1043.4587 16.9609
0.3792
VDWAALS -1260.6967 21.1303
0.4724
EEL -10391.9146 91.2581
2.0401
1-4 VDW 613.1946 10.2166
0.2284
1-4 EEL 3505.3632 36.2022
0.8093
EGB -1945.1404 80.9295
1.8092
ESURF 74.1155 2.3330
0.0522
G gas -4429.3539 99.8310
2.2317
G solv -1871.0249 79.3139
1.7731
TOTAL -6300.3789 41.4504
0.9266
Ligand:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 387.6692 16.7066
0.3735
ANGLE 1045.6809 25.4881
0.5698
DIHED 692.4324 13.7993
0.3085
VDWAALS -952.7555 14.5903
0.3262
EEL -8641.7292 91.5995
2.0477
1-4 VDW 461.2082 9.1231
0.2039
1-4 EEL 4939.3351 28.4739
0.6365
EGB -2231.0741 82.6957
1.8487
ESURF 54.4739 1.3181
0.0295
G gas -2068.1589 91.0262
2.0349
G solv -2176.6002 82.2126
1.8379
TOTAL -4244.7592 33.0711
0.7393
Differences (Complex - Receptor - Ligand):
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 0.0000 0.0001
0.0000
ANGLE 0.0000 0.0000
0.0000
DIHED -0.0141 0.0241
0.0005
VDWAALS -99.8535 6.0980
0.1363
EEL -159.8731 36.9519
0.8261
1-4 VDW 0.0000 0.0000
0.0000
1-4 EEL -0.0000 0.0001
0.0000
EGB 190.3220 34.0912
0.7621
ESURF -12.5819 0.7628
0.0171
DELTA G gas -259.7407 37.9983
0.8495
DELTA G solv 177.7401 33.6728
0.7528
DELTA TOTAL -82.0007 8.8080
0.1969
-------------------------------------------------------------------------------
-------------------------------------------------------------------------------
POISSON BOLTZMANN:
WARNING: INCONSISTENCIES EXIST WITHIN INTERNAL POTENTIAL
TERMS. THE VALIDITY OF THESE RESULTS ARE HIGHLY QUESTIONABLE
Complex:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 943.6271 26.7114
0.5971
ANGLE 2550.9637 39.6714
0.8869
DIHED 1735.8770 22.1045
0.4941
VDWAALS -2313.3056 27.5916
0.6168
EEL -19193.5169 134.4839
3.0064
1-4 VDW 1074.4028 13.9567
0.3120
1-4 EEL 8444.6983 46.6150
1.0421
EPB -3639.1951 114.6465
2.5629
ENPOLAR 2428.9904 15.1091
0.3378
EDISPER -1465.9844 20.3883
0.4558
G gas -6757.2536 141.2106
3.1568
G solv -2676.1891 116.1703
2.5970
TOTAL -9433.4427 61.0423
1.3646
Receptor:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 555.9580 20.4648
0.4575
ANGLE 1505.2828 30.5134
0.6821
DIHED 1043.4587 16.9609
0.3792
VDWAALS -1260.6967 21.1303
0.4724
EEL -10391.9146 91.2581
2.0401
1-4 VDW 613.1946 10.2166
0.2284
1-4 EEL 3505.3632 36.2022
0.8093
EPB -1787.8322 77.6149
1.7351
ENPOLAR 1441.4144 12.1118
0.2708
EDISPER -921.0981 16.5931
0.3709
G gas -4429.3539 99.8310
2.2317
G solv -1267.5159 80.0736
1.7901
TOTAL -5696.8698 45.0841
1.0079
Ligand:
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 387.6692 16.7066
0.3735
ANGLE 1045.6809 25.4881
0.5698
DIHED 692.4324 13.7993
0.3085
VDWAALS -952.7555 14.5903
0.3262
EEL -8641.7292 91.5995
2.0477
1-4 VDW 461.2082 9.1231
0.2039
1-4 EEL 4939.3351 28.4739
0.6365
EPB -2061.1500 81.6911
1.8262
ENPOLAR 1056.5828 6.3143
0.1412
EDISPER -679.6138 7.4369
0.1663
G gas -2068.1589 91.0262
2.0349
G solv -1684.1810 81.4186
1.8201
TOTAL -3752.3399 36.6296
0.8189
Differences (Complex - Receptor - Ligand):
Energy Component Average Std. Dev. Std. Err. of
Mean
-------------------------------------------------------------------------------
BOND 0.0000 0.0001
0.0000
ANGLE 0.0000 0.0000
0.0000
DIHED -0.0141 0.0241
0.0005
VDWAALS -99.8535 6.0980
0.1363
EEL -159.8731 36.9519
0.8261
1-4 VDW 0.0000 0.0000
0.0000
1-4 EEL -0.0000 0.0001
0.0000
EPB 209.7871 34.7650
0.7772
ENPOLAR -69.0068 3.6463
0.0815
EDISPER 134.7275 5.4875
0.1227
DELTA G gas -259.7407 37.9983
0.8495
DELTA G solv 275.5078 35.5314
0.7943
DELTA TOTAL 15.7671 13.6230
0.3045
-------------------------------------------------------------------------------
-------------------------------------------------------------------------------
The attached is the pdb file for the systems. Any advice or suggestions
would be greatly appreciated.
Best,
Yang
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Wed Mar 06 2024 - 16:30:02 PST
