Non equilibrium alchemical transformations - Creation - couple-intramol=no

GROMACS version: 2021.3
GROMACS modification: Yes (plumed)

Hi, I am doing non equilibrium alchemical transformations. When annihilating a ligand from the protein pocket with rlist=2.2 and couple-intramol=no everything works fine. But when creating the same ligand in a box of equilibrated water with rlist=2.2 and couple-intramol=no I get:

Fatal error:
There are 1 perturbed non-bonded pair interactions beyond the pair-list cutoff
of 2.2 nm, which is not supported. This can happen because the system is
unstable or because intra-molecular interactions at long distances are
excluded. If the latter is the case, you can try to increase nstlist or rlist
to avoid this.The error is likely triggered by the use of couple-intramol=no
and the maximal distance in the decoupled molecule exceeding rlist.

The problem is that I am sure that the ligand perfectly fits in rlist and rlist is actually big enough to mostly fit the whole water box (4 X 4 X 4 nm circa).

I have tried to proceed the creation with different speeds but it didn’t change

And the problem doesn’t happen 100% of the time and often if I re-run the transformation it arrives to the end without problems.

Does someone have an idea/solution for the problem? (without changing couple-intramol)

ps I am creating vdw and q separately and it happens in both situations

One thing to check is that
" the initial lambda is chosen as zero, and delta-lambda (per MD step) is set such that at the end of the simulation lambda is at 1 (1 / nsteps)" : Mutation Free Energy Calculations tutorial - BioExcel Building Blocks

Hi Maurice,
I had the same problem when calculating the solvation free energy of a molecule and I’m wondering if you have solved the problem. (I was using GROMACS 2021.4 with PLUMED.)

The issue seems to be a bug in the current GROMACS version, if I understand correctly:
https://manual.gromacs.org/documentation/nightly/release-notes/2021/major/bugs-fixed.html

Here is an relevant issue about the problem that is also linked in the article above: solvation free energy with couple-intramol set to no - Redmine #3403 (#3403) · Issues · GROMACS / GROMACS · GitLab

It seems that the bug has been fixed for the next GROMACS release, but I’m not sure if there are workarounds for the ones that are using GROMACS 2021.

Hi, sorry for my late reply.
In my case in the end it came out that the solution was as easy as it gets, in fact I didn’t equilibrate my system properly, and now everything works.

@wehs7661 The error that you are talking about should be already solved in gromacs 2021 for what I know