gromacs 2021.4 on x86_64, intel i5-4200M, no GPU playing with a simple model system for free energy calculations i came across an issue, possibly related to pair-list generation, and the PBC implementation, when free-energy=yes. You might argue that this is a somewhat pathological system to start with, but my results do point out an issue that should be fixed, at least with a warning, or a more meaningful error message. My system is but a single hybrid molecule in vacuum, and what I see is that I get a fatal error (see below) when I start with my molecule centered at the origin (em.pdb), but not when it is in the center of the box (ems.pdb), with the molecule's conformation and all other input files being exactly the same in both cases. gmx grompp -f md0.mdp -c ems.pdb -p fe.top -o center.tpr -maxwarn 1 gmx mdrun -v -deffnm center finishes gracefully gmx grompp -f md0.mdp -c em.pdb -p fe.top -o origin.tpr -maxwarn 1 gmx mdrun -v -deffnm origin gives: Fatal error: There are 103 perturbed non-bonded pair interactions beyond the pair-list cutoff of 0.99 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. files attached. [case.tgz](/uploads/8d3a9709b80e9698843abc753cc20d40/case.tgz)