ProteoKnot · Entangled tertiary folds

The most sophisticated functions of proteins emerge at the level of their tertiary structure and involve large amplitude conformational changes. In contrast, the functions of synthetic molecules are currently limited by our inability to control their structure beyond the level of static secondary structures. ProteoKnot seeks to address this limitation by introducing entanglements as a tool to control tertiary folding while maintaining the flexibility required to allow them to change conformation. The first objective of this project is to establish design principles to guide the construction of entangled tertiary folds. These principles will be tested with the assembly of multiply-stranded helices (WP1), entangled macromolecules (WP2) and polymers (WP3). The second objective is to introduce photoswitchable handles in these structures to enable remote control over their conformational states (WP4). Operating the transition from the traditional design of static secondary folds to the design of dynamic tertiary folds will unlock the possibility to engineer increasingly complex macromolecules with protein-like functions. These exquisite architectures feature tandem helical motifs and cavities, providing an avenue toward highly elaborated receptors and catalysts. To illustrate the great potential of entangled tertiary folds for future applications, our third objective will be to develop their use as multi-responsive switchable catalysts (WP5).