In the so called additive QM/MM scheme the fundamental assumption is that the system is the sum of two subsystems, one of quantum nature (QM subsystem), integrated by those atoms whose electronic effects are essential to correctly describe the behavior of the system, and other of classical nature (MM subsystem). The energy of the system is then calculated as the sum of the QM energy of the quantum subsystem (E QM ), the MM energy of the classical subsystem (E MM ), and the QM/MM energy that describes the interaction between the two subsystems: