Yang,
In addition to Adrian's comment:
(1) When using igb=2, you need to set default PBradii to mbondi2 in tLEaP
(see the manual, Section 4.1); and
(2) You should use OPC water and not TIP3P with ff19SB (although this is
secondary to your issues).
Cheers,
Todd
On Wed, Mar 6, 2024 at 6:14 PM Yang Wei via AMBER <amber.ambermd.org> wrote:
> 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
> _______________________________________________
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>
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Received on Wed Mar 06 2024 - 18:00:02 PST
