Free energy/dual topologies/exclusions

User discussions
1

GROMACS version:2021.4
GROMACS modification: No

Hi,
I would like to calculate a relative binding free energy difference between two
ligands in a protein’s binding site, and I am struggling with the topology there.
The ligands are similar, but have a portion that changes. I want to set up a dual
topology approach. And here I have to make sure that the atoms in
the two parts of the ligand that are different in topology A (lambda=0) and B (lambda=1), do not interact, as they basically overlap. Now, do I have to define
the corresponding exclusions explicitely/manually, or is this perhaps done
automatically by the free energy implementation?

I understand that this question wouid not arise if I used a single topology
approach , but this would not work here because I’d have to turn constraints
into harmonic bonds, and vice versa.

On a related note: when googling for answers to this question I came across
a relatively recent discussion of the developers:

If one of the involved people happens to read this, please let me know whether
the issues discussed there might affect the type of calculation I describe here!

And another one - there is this paper:
https://pubs.acs.org/doi/pdf/10.1021/acs.jpcb.8b04187?rand=hutxa8ul
Can anybody enlighten me - is this related to the discussion on github
linked above, or is this something entirely different?

thanks,
michael

2

Yes, the gitlab issue has this use case and several solution.

If all interactions between the two ligands are within the cut-off, the simplest solution is likely to put both ligands in a single moleculetype and use exclusions to exclude all atom pairs between the two ligands.

3

Thanks for the reply!
My ligand, when fully extended is about 18Angstrom long. If I understood
the issue correctly, this means I’d have to use a cut-off at least that large (18A).
BTW are we talking about rlist here, or rcoulomb, or both?
cheers,
Michael

4

For perturbed atoms it’s rlist.

The other option is the different LJ parameter trick mentioned on gitlab.

5

I’ll just use a larger rlist for now then, if I leave rcoulomb and rvdw at,
say, 12Angstrom, and use a larger nstlist (~40) the performance penalty I pay
for that is probably small.
I am not sure i fully understood the other option, it certainly sounds like
something that would need to be automated, doing that by hand could be
quite error-prone.
thanks again!
michael