The short-range contribution consists of the interaction between the electron density and nuclear (or core) charges of the QM subsystem and the effective point charges (or multipoles) in the short-range domain. The latter includes all MM atoms within a given distance from the QM subsystem. The long-range interaction is computed using a multipole expansion of the electrostatic potential originating from the QM subsystem. This greatly reduces the computational cost of the evaluation of electrostatic QM-MM interactions for large molecular systems (which can be of the order of 10 5 atoms or more). MiMiC supports a generalized version of the approach by Laio et al. allowing, in principle, any order of multipoles to be used. This can potentially increase the precision of the long-range interactions and thus allow for a reduction of the number of atoms in the short-range domain. The original implementation by Laio et al. was later extended to three coupling regions to achieve a similar reduction, using dynamically generated restrained electrostatic potential (D-RESP) charges to describe interactions with MM atoms in an intermediate domain. This extension is especially useful for elongated QM subsystems which we will address in a further development of our implementation.