(4.2.11) Gao : A general approach that goes beyond QM/MM are the fragment-based methods. In 2013, we edited a special issue of Accounts of Chemical Research on this topic. Fragment-based methods such as the explicit polarization (X-Pol) model can be designed as general QM/QM embedding approaches in which each fragment can be individually represented by any electronic-structure method, with the inclusion of the instantaneous environmental effects through Hartree, Pauli exchange, and dispersion potentials. Importantly, X-Pol and other fragment-based methods provide a framework for the development of next-generation quantum-mechanics force fields (QMFFs) for condensed-phase and biomolecular simulations. In a QMFF, QM effects such as polarization, charge transfer, and the change of the potential-energy surface itself due to dynamical fluctuations as well as chemical reactions are naturally included. These effects would be very difficult, if not impossible, to describe using the current MM force fields.