  We present a protocol for the fully automated construction of quantum
mechanical-(QM)-classical hybrid models by extending our previously reported
approach on self-parametrizing system-focused atomistic models (SFAM) J. Chem.
Theory Comput. 2020, 16, 1646]. In this QM/SFAM approach, the size and
composition of the QM region is evaluated in an automated manner based on first
principles so that the hybrid model describes the atomic forces in the center
of the QM region accurately. This entails the automated construction and
evaluation of differently sized QM regions with a bearable computational
overhead that needs to be paid for automated validation procedures. Applying
SFAM for the classical part of the model eliminates any dependence on
pre-existing parameters due to its system-focused quantum mechanically derived
parametrization. Hence, QM/SFAM is capable of delivering a high fidelity and
complete automation. Furthermore, since SFAM parameters are generated for the
whole system, our ansatz allows for a convenient re-definition of the QM region
during a molecular exploration. For this purpose, a local re-parametrization
scheme is introduced, which efficiently generates additional classical
parameters on the fly when new covalent bonds are formed (or broken) and moved
to the classical region.
