Designing the structure and folding pathway of modular topological bionanostructures

Polypeptides and polynucleotides are programmable natural polymers whose linear sequence can be easily designed and synthesized by the cellular transcription/translation machinery. Nature primarily uses proteins as the molecular machines and nucleic acids as the medium for the manipulation of heritable information. A protein's tertiary structure and function is defined by multiple cooperative weak long-range interactions that have been optimized through evolution. DNA nanotechnology uses orthogonal pairwise interacting modules of complementary nucleic acids as a strategy to construct defined complex 3D structures. A similar approach has recently been applied to protein design, using orthogonal dimerizing coiled-coil segments as interacting modules. When concatenated into a single polypeptide chain, they self-assemble into the 3D structure defined by the topology of interacting modules within the chain. This approach allows the construction of geometric polypeptide scaffolds, bypassing the folding problem of compact proteins by relying on decoupled pairwise interactions. However, the folding pathway still needs to be optimized in order to allow rapid self-assembly under physiological conditions. Again the modularity of designed topological structures can be used to define the rules that guide the folding pathway of long polymers, such as DNA, based on the stability and topology of connected building modules. This approach opens the way towards incorporation of designed foldamers in biological systems and their functionalization.