The reaction energy with increasing QM region size was then calculated and evaluated for the different schemes and compared to the distance-based case (see Fig. ). It can be clearly seen that the single inclusion scheme (reactant single and reaction single) does not work properly, since we observe a worse convergence behavior than for the distance-based inclusion (distance). This underlines the expectation that always including complete base pairs to the QM region is necessary to gain reasonable results in DNA systems. Both pairwise inclusion schemes (reactant pairs and reaction pairs) lead to a similar convergence as for distance-based inclusion. Starting from 5 bp, both reaction energies converge at about 27.4 kcal/mol. At first glance, sbPCVA seems to be not necessary for QM region construction since it resembles the distance-based results. But it can be helpful to estimate the distancedependent decrease in the strength of the effect on the target base with no need to perform QM/MM calculations for medium-to large-sized QM regions. The sensitivities can be helpful to consider which distant base pairs still have a high impact on the target base pair and which ones can be neglected in a productive QM/MM run. Especially for larger and more complex DNA structures than the helix used in this work, for instance DNA origami structures, sbPCVA could be a useful tool to quantify base-dependent effects.