# Free energy/dual topologies/exclusions

**URL:** <https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146>\
**Category:** User discussions\
**Created:** [November 15, 2021, 8:49pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146 "2021-11-15T20:49:13Z")\
**Posts on this page:** 5\
**Page:** 1

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**Author:** ![michael.brunsteiner](https://avatars.discourse-cdn.com/v4/letter/m/7cd45c/32.png) [@michael.brunsteiner](https://gromacs.bioexcel.eu/u/michael.brunsteiner)\
**Post date:** [November 15, 2021, 8:49pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146/1 "2021-11-15T20:49:13Z")

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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:

> **[Exclusions not treated correctly for the interactions beyond rcoulomb (#4051)...](https://gitlab.com/gromacs/gromacs/-/issues/4051)**
>
> If an interaction between two atoms is excluded in the topology, but the interatomic distance between the atoms is larger than rcoulomb, the interaction will not be properly...

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](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

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**Author:** ![hess](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/hess/32/416_2.png) [@hess](https://gromacs.bioexcel.eu/u/hess)\
**Post date:** [November 17, 2021, 1:25pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146/2 "2021-11-17T13:25:54Z")

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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.

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**Author:** ![michael.brunsteiner](https://avatars.discourse-cdn.com/v4/letter/m/7cd45c/32.png) [@michael.brunsteiner](https://gromacs.bioexcel.eu/u/michael.brunsteiner)\
**Post date:** [November 18, 2021, 12:44pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146/3 "2021-11-18T12:44:45Z")

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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

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<div class="post-metadata">

**Author:** ![hess](https://dub1.discourse-cdn.com/flex017/user_avatar/gromacs.bioexcel.eu/hess/32/416_2.png) [@hess](https://gromacs.bioexcel.eu/u/hess)\
**Post date:** [November 18, 2021, 6:42pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146/4 "2021-11-18T18:42:13Z")

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For perturbed atoms it’s rlist.

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

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<div class="post-metadata">

**Author:** ![michael.brunsteiner](https://avatars.discourse-cdn.com/v4/letter/m/7cd45c/32.png) [@michael.brunsteiner](https://gromacs.bioexcel.eu/u/michael.brunsteiner)\
**Post date:** [November 18, 2021, 9:06pm UTC](https://gromacs.bioexcel.eu/t/free-energy-dual-topologies-exclusions/3146/5 "2021-11-18T21:06:38Z")

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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