The workflow of a simulation employing the MiMiC framework is not predetermined but can be adapted to the multiscale implementation being implemented and to the chosen external programs. In the QM/MM implementation of this work, we use the workflow illustrated in Figure . Here the CPMD program is the main simulation driver and QM engine while GROMACS is the MM engine. Both programs are executed independently and run simultaneously using MiMiC to communicate and to compute QM/MM contributions. In the initialization phase, the programs read their respective input files, MiMiC collects data from GROMACS and CPMD, and sends the necessary data to CPMD, e.g. coordinates, atom types, etc., to allow setup of data structures. Once CPMD is initialized, the QM/MM-MD loop is entered. The loop consists of several stages. The first one involves the sending of A MiMiC-based QM/MM simulation using CPMD and GROMACS runs one instance of each program. GROMACS computes all contributions related to the MM subsystem as well as the classical nonbonded van der Waals QM-MM interactions and, if present, bonded QM-MM interactions. The GROMACS input thus includes the entire system, i.e. QM subsystem is also described by the MM force field. The atoms belonging to the QM subsystem are added to a special index group within GROMACS which will have the following effect: a) point charges of the atoms belonging to the group are zeroed, b) nonbonded van der Waals interactions between atoms in the group are excluded, and c) bonds between atoms in the group are deleted. This avoids treating interactions twice, i.e. at MM level and at the QM level. In cases where the MM engine does not allow such operations intrinsically, MiMiC can follow a different approach where two instances of the MM engine run simultaneously. The first instance runs an MM calculation of the entire system while the second instance runs an MM calculation only including atoms belonging to the QM subsystem. The point charges of QM atoms are set to zero in both instances. The energies and forces computed by the second instance are then subtracted from those computed by the first one. This approach has a minor computational overhead since the cost of the additional MM calculation of the (typically small) QM subsystem is negligible. Moreover, it allows CPMD to be used together with virtually any external program, thus opening access to a large number of force fields.