can be used. The protein is cut into fragments of one or more amino acids at the peptide bonds, and the severed bonds are capped with acetyl (ACE) groups and N-methylamide (NME) capping groups, respectively, to preserve their chemical environment. In Eq. ( ), First benchmark applications demonstrated that by fully optimizing the electron densities of all subsystems in the presence of the protein environment 3-FDE provides electron densities and electrostatic potentials that are significantly more accurate than those calculated with the MFCC fragmentation scheme. The 3-FDE scheme has been used to obtain optimized electron densities for the the Fenna-Matthews-Olson protein, which where then used as environment in calculations of the embedded chromophores with FDEu-TDDFT . This can be further combined with a continuum solvation model for the outer environment , for which an efficient local COSMO scheme has Figure : By mapping the expected error due to the fragmentation between two amino acids to a graph (left) it becomes possible to apply graph partitioning algorithms to identify optimal fragmentations that minimize this error (right). Here, such a scheme is illustrated for the protein ubiquitin. Adapted with permission from Ref. . Copyright 2021 American Chemical Society.