[gmx-users] Relative Binding Free Energy Calculation

[Robert Johnson]

Hello everyone,
When performing a relative binding free energy calculation, I
understand that it is a good practice to separate the transformation
of charges of the ligand and the transformation of vdW parameters into
two calculations. However, is it advisable to completely discharge the
ligand before transforming vdW parameters? For example, should the
calculation proceed as:
1. Reduce all ligand charges to zero
2. Transform vdW parameters for relevant atoms
3. Recharge ligand atoms with the new, appropriate values

It seems to me that steps 1 and 3 would yield large free energy
changes, thus making the calculation of free energy differences
between the bound and unbound states more difficult due to convergence
issues. Is it more advisable to proceed as:
1. Reduce charges to zero on ONLY those ligand atoms that will have
their vdW parameters transformed
2. Transform vdW parameters for relevant atoms
3. Transform charges on ligand to their new, appropriate values

Proceeding in this way seems like you would obtain smaller free energy
changes for steps 1 and 3 and could result in better convergence for
free energy differences. Any suggestions?

Thanks,
Bob