More generally, network analysis offers a promising framework for systematic QM region construction. Here, we employed the construction of graphs based on the correlated motion of the amino acid residues, which allows for the identification of allosteric pathways. Other schemes for the construction of graphs, e.g. based on electrostatic interactions, could be considered and subjected to the tools of network analysis to minimize the error introduced by QM/MM schemes. Work along these lines is currently in progress in our group.