Loose coupling has the implicit advantage of providing great flexibility and low maintenance efforts, but typically requires more efforts in the planning stage. Using this approach, it is relatively easy to couple independent programs, thus giving access to new features as they become available in a code, potentially without requiring any modifications in the other coupled codes. This substantially accelerates the availability of new methodological and technical developments. Moreover, the increased flexibility also facilitates the development of new multiscale approaches that go beyond QM/MM. One limiting factor, however, is that computational efficiency can be hampered by the communication between the coupled codes. For example, in the file-based approach, in which the communication between codes is handled by writing/reading files, there is computational overhead stemming from file input/output operations and initialization/termination of external programs. This is the general path taken by several popular classical MD packages, such as AMBER, GRO-MACS, and NAMD, as well as the PUPIL system 24 and ChemShell environment. However, AMBER also provides a more efficient interface based on message passing interface (MPI), and ChemShell has the option to directly link certain external codes in order to increase computational efficiency.