Protein-based Engineered Nanostructures

Igor Drobnak, Ajasja Ljubetič, Helena Gradišar, Tomaž Pisanski, Roman Jerala

Aitziber L. Cortajarena, Tijana Z. Grove

Proteins are highly perfected natural molecular machines, owing their properties to the complex tertiary structures with precise spatial positioning of different functional groups that have been honed through millennia of evolutionary selection. The prospects of designing new molecular machines and structural scaffolds beyond the limits of natural proteins make design of new protein folds a very attractive prospect. However, de novo design of new protein folds based on optimization of multiple cooperative interactions is very demanding. As a new alternative approach to design new protein folds unseen in nature, folds can be designed as a mathematical graph, by the self-assembly of interacting polypeptide modules within the single chain. Orthogonal coiled-coil dimers seem like an ideal building module due to their shape, adjustable length, and above all their designability. Similar to the approach of DNA nanotechnology, where complex tertiary structures are designed from complementary nucleotide segments, a polypeptide chain composed of a precisely specified sequence of coiled-coil forming segments can be designed to self-assemble into polyhedral scaffolds. This modular approach encompasses long-range interactions that define complex tertiary structures. We envision that by expansion of the toolkit of building blocks and design strategies of the folding pathways protein origami technology will be able to construct diverse molecular machines.