No polar solvation energy

[Mara Cruz]

Hi,

I performed MD simulations in GROMACS with a membrane protein and four different peptide ligands using CHARMM36m ff, after embedding the system in a POPC membrane using CHARM-GUI. 

For the gmx_MMPBSA calculation, I removed the water, ions and membrane lipids, and used an implicit membrane. 

I got no errors but I thought the deltaG values were very negative and then I noticed in the results file that the polar solvation energy was not being computed. 

Delta (Complex - Receptor - Ligand):
Energy Component       Average     SD(Prop.)         SD   SEM(Prop.)        SEM
-------------------------------------------------------------------------------

...

ΔVDWAALS                -54.57          0.95       5.03         0.09       0.50
ΔEEL                    -32.27          3.70       4.76         0.37       0.47
Δ1-4 VDW                  0.00          2.20       0.00         0.22       0.00
Δ1-4 EEL                  0.00          9.27       0.00         0.92       0.00
ΔEPB                      0.00          0.00       0.00         0.00       0.00
ΔENPOLAR                 -8.99          0.02       0.34         0.00       0.03
ΔEDISPER                  0.00          0.00       0.00         0.00       0.00

ΔGGAS                   -86.84          4.49       6.19         0.45       0.62
ΔGSOLV                   -8.99          0.02       0.34         0.00       0.03

ΔTOTAL                  -95.83          4.49       6.20         0.45       0.62


This was the command I used:
nohup mpirun -np 20 gmx_MMPBSA MPI -O -i mmpbsa.in -cs production.tpr -ci index.ndx -cg 17 18 -ct mmpbsa_test_490-500ns.xtc -cp topol.top -o prod.dat -do prod_decomp.dat -eo prod_energy.csv -deo prod_energy_decomp.csv > mmpbsa.log 2>&1 &

I'm sending the google drive link with all the files:
https://drive.google.com/drive/folders/1E7LY4oxC_SNqeXxnP_1heeU2ojnyedNm?usp=drive_link

[mariosergi...@gmail.com]

Hi Mara. 

In your calculation, ΔEPB = 0.00 is expected for PB calculations with an implicit membrane in gmx_MMPBSA. It does not necessarily mean that the PB polar solvation contribution was not computed.

For PB membrane calculations, the PB reaction-field contribution is not printed separately as EPB; instead, it is included in the electrostatic term EEL. Therefore, in this type of calculation, ΔEEL contains both the Coulombic electrostatic contribution and the PB reaction-field contribution.

So, in your output:

ΔEEL = -32.27
ΔEPB = 0.00
ΔTOTAL = -95.83

ΔEPB = 0.00 should not be interpreted as missing polar solvation. It means that the PB polar contribution is folded into ΔEEL.

However, an important point is that the value reported as:

ΔTOTAL = -95.83 kcal/mol

corresponds only to the enthalpic MM/PBSA contribution, because no entropy term was included. In other words, this is not the complete binding free energy:

ΔGbinding ≠ ΔTOTAL

Rather, in this case:

ΔTOTAL ≈ ΔHbinding

or more precisely, the MM/PBSA enthalpic contribution to binding.

For peptide ligands, the omitted entropy term can be substantial, especially because peptides often lose considerable translational, rotational, and conformational freedom upon binding. Therefore, very negative ΔTOTAL values are not unusual when entropy is neglected, and they should not be interpreted directly as experimental binding free energies.

The result is still useful for relative comparison among the four peptide ligands, provided that all systems were processed with the same protocol and comparable trajectory sampling. But the values should be described as relative enthalpic binding contributions, not absolute binding free energies.

I would suggest checking the following points:

1. Confirm that receptor and ligand groups were correctly selected.
2. Verify that all four peptide systems were processed with the same MM/PBSA protocol.
3. Inspect whether the large negative value is mainly driven by ΔVDWAALS, ΔEEL, or both.
4. Check the implicit membrane parameters, especially the membrane center and the membrane thickness.
5. Avoid overinterpreting ΔGGAS and ΔGSOLV separately, because in membrane PB calculations, the PB polar contribution is folded into EEL.
6. Report clearly that the entropic contribution was not included.

In short, the polar PB contribution is not missing. In implicit membrane PB calculations, EPB is reported as zero because it is merged into EEL. Also, since entropy was not calculated, the reported ΔTOTAL should be interpreted as an enthalpic MM/PBSA contribution, not as the complete binding free energy.

Generated with gmx_MMPBSA-GPT (https://chatgpt.com/g/g-EQdUjhBwP-gmx-mmpbsa-gpt). Please contact the developers if you cannot solve the issue using this information.