charmm36 force field and positive binding energy

[faryal....@gmail.com]

Dear g_mmpbsa users

I sent an email before about calculated positive binding energy of my complex composed of a protein and a peptide ligand which had 2 phosphotyrosine residues using g_mmpbsa, but didnt get any reply. So decided to send another mail with details, because I calculated many other complexes without any phosphorylated residue using OPLS all atom force field by Gromacs 2016.4 and pdie = 2 and got minus binding free energy, but this time I ran a md simulation on my complex using charmm36 all atom force field with different solute die electrics ( 4, 2, 1) but obtained positive binding free energy. I dont know is it because of charmm36 force field or the presence of phosphate groups? I would really appreciate it if anyone helps me.
 
The details of my work is following as:
 In according to this article:

Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations

 First of all, I considered  pdie = 4 , since total charge of the receptor is -8 and there are 4 charged residues (1 Asn, 2 Lys and 1 Arg) in the allosteric site of the receptor (interaction interface) and total charge of the peptide ligand is -4 and there are 2 phosphotyrosine and 1 histidine residues in the ligand and interaction interface. In addition, there are 2 electrostatic interactions in the interaction interface between :

Lys:NZ and Tyr:O2P
Arg:NE and Tyr:O2P

but the calculated binding free energy was:

 van der Waal energy      =        -174.958   +/-   14.651 kJ/mol

 Electrostattic energy    =        -246.763   +/-   69.969 kJ/mol

 Polar solvation energy   =        1020.060   +/-  143.346 kJ/mol

 SASA energy              =         -26.030   +/-    1.928 kJ/mol

 SAV energy               =           0.000   +/-    0.000 kJ/mol

 WCA energy               =           0.000   +/-    0.000 kJ/mol

 Binding energy           =         572.309   +/-   79.069 kJ/mol

So, the second time , I considered pdie = 2 , and the calculated binding energy was:

van der Waal energy      =        -166.543   +/-   19.850 kJ/mol

 Electrostattic energy    =        -510.476   +/-  124.878 kJ/mol

 Polar solvation energy   =        1128.754   +/-  139.815 kJ/mol

 SASA energy              =         -25.564   +/-    2.265 kJ/mol

 SAV energy               =           0.000   +/-    0.000 kJ/mol

 WCA energy               =           0.000   +/-    0.000 kJ/mol

 Binding energy           =         426.170   +/-   52.031 kJ/mol
 
The third time, considered pdie = 1 , binding energy was calculated :

 van der Waal energy      =        -174.958   +/-   14.651 kJ/mol

 Electrostattic energy    =        -987.050   +/-  279.876 kJ/mol

 Polar solvation energy   =        1180.114   +/-  165.293 kJ/mol

 SASA energy              =         -26.030   +/-    1.928 kJ/mol

 SAV energy               =           0.000   +/-    0.000 kJ/mol

 WCA energy               =           0.000   +/-    0.000 kJ/mol

 Binding energy           =          -7.924   +/-  133.381 kJ/mol
 

[g_mmpbsa Mailing List]

As I noted, you got response to your previous mail so I don't know which mail you are talking about. Apart from that, for your present query, we have not tested the g_mmpbsa with charmm36 so we can't say about the validity. Other members of g_mmpbsa tool, also previously reported about the positive binding energy when using charmm36 force field.

[faryal....@gmail.com]

Thank you for your reply

Ok. But would you please advice me how could I calculate the  free binding energy of my complex (receptor and ligand that has 2 phosphotyrosine residues ) which has been simulated by charmm36 all atom force field?