Designing the structure and folding pathway of modular topological bionanostructures

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Polypeptides (proteins) and polynucleotides (nucleic acids) are programmable polymers essential for biological functions.
• Protein structure and function arise from complex interactions, while DNA nanotechnology constructs 3D structures using nucleic acid interactions.
• Designing functional protein structures is challenging due to complex folding pathways.

Purpose of the Study:

• To apply modular interaction strategies, inspired by DNA nanotechnology, to polypeptide design.
• To create self-assembling polypeptide scaffolds with defined 3D structures.
• To explore methods for optimizing folding pathways for rapid self-assembly under physiological conditions.

Main Methods:

• Utilizing orthogonal dimerizing coiled-coil segments as interacting modules for polypeptide chains.
• Concatenating modules to enable self-assembly into predefined 3D structures based on interaction topology.
• Leveraging modularity to define folding rules for long polymers, guiding self-assembly based on building module stability and topology.

Main Results:

• Demonstrated the construction of geometric polypeptide scaffolds by decoupling pairwise interactions.
• Showcased an approach to bypass the folding problem of compact proteins.
• Established that designed topological structures can guide the folding pathway of long polymers.

Conclusions:

• Modular design strategies can create self-assembling polypeptide structures.
• This approach offers a pathway to design foldamers for integration into biological systems.
• Functionalization of designed foldamers presents future possibilities for synthetic biology and protein engineering.