[gmx-users] Free Energy of Binding Question

[Abdülkadir KOÇAK]

Dear GMX Community,

I am aiming to compare the relative binding energy (BE) of a ligand to wild type (WT) vs mutant (MUT) protein and thus trying to run a Free Energy Calculation for the binding energy of the ligand to both proteins (WT and MUT) using Bennett Acceptance Ratio (BAR).

As the first step, I calculated decoupling of the ligand from both proteins in two seperate MD runs by first turning off the coulombic interaction and then the van der waals interaction. The next step would be the solvation free energies of the ligand in order to get the correct BE. However, the ligand is the same for both WT and MUT, so in terms of getting relative BE, should we still calculate the ligand in water or will the ligand solv energies will cancel in the DDG=DG(WT)-DG(MUT)?

Besides, from the decoupling of the Protein-ligand complex, I am getting very high DG values (1134 kJ/mol). Is this meaningful or not?

Thx