I had a look at the system. I don’t see any apparent problems. But the distance between the water hydrogen 3897 to the metal is only 2.30 Å. What metal is this? It says CA, but I guess it’s not a Ca2+ ion, right? Especially since the QM optimized water is orienting its hydrogen atom towards it. What is its VdW radius? Is it correctly parameterized in the force field?
I’m still quite sure it’s the input structure that’s the problem. Without the topology and mdp parameters I’m afraid I cannot help you much more at the moment. Using define = -DFLEXIBLE was mainly to see if applying constraints from an unfavorable structure caused any problems. Since it did not help there’s no reason to retain it.