The PDE model has so far only been considered for solute-solvent systems. When tackling large molecular systems, fragmentation of the environment can be used to circumvent the poor scaling of the underlying methods used to derive the embedding potential. This is the approach used in both the PE and PDE models, as detailed above for the latter. For solute-solvent systems, the selection of individual molecules as fragments is straightforward, but more care is needed when treating typical biological macromolecules such as proteins, which often contain several thousands of atoms. For such systems, the fragmentation method needs to handle the cutting of covalent bonds. In the PE model, inspired by the work of Ryde and coworkers, the method of molecular fractionation with conjugate caps (MFCC) was adopted to partition larger molecules into small, computationally manageable fragments. Specifically, Söderhjelm and Ryde 33 used the method to calculate localized properties (multipoles and polarizabilities) of proteins in order to derive a highly accurate force field.