Dagliyan, O. et al. Nat. Commun. 9, 4042 (2018).

Optogenetic and chemogenetic tools represent a powerful suite of technologies for controlling cellular behavior and studying protein function. One approach for generating proteins that can be regulated by a researcher is to make split versions of a protein and then fuse the individual pieces to proteins that dimerize; dimerization can be induced by either light or small-molecule treatment. However, it has been challenging to design constructs that can reassemble efficiently without high levels of spontaneous assembly. Dagliyan and colleagues developed an approach called “split proteins regulated by a ligand or by light” (SPELL) to computationally identify split sites on the basis of the ‘split energy’ of the protein. They show that their approach works robustly for a range of enzymes including a tyrosine kinase, TEV proteinase, and a guanine exchange factor.