We chose a B-DNA system (PDB: 1ZEW , see Fig. ) with 10 basepairs (bp) as test system, which was also used in the work on QM/MM energy convergence by Roßbach and Ochsenfeld . In line with Ref. 18, we do not perform geometry optimizations for this system, but directly start with single point calculations on the given structure differing from the procedure in the protein case. Due to the lack of substrates in this system the minimal QM region is represented by the two bases G7 and C14 performing a proton-transfer reaction (highlighted in Fig. ).