Assembly of Protein‐DNA Framework Nanostructures: Structurally Defining Protein‐DNA Interfaces With Aptamer

Abstract

ABSTRACT DNA and proteins have been extensively explored for self‐assembly of nanostructures. Each has its own advantages and limitations. By integrating them together, protein‐DNA frameworks (PDFs) could potentially combine their advantages while overcoming the limitations associated with each component; thus, providing a huge diversity in terms of structures, functionalities, assembly versatilities, and responsiveness. Though each has been demonstrated to self‐assemble into large structures, it remains a great challenge to engineer well‐structured protein‐DNA interfaces for PDF assembly. Herein, we report a robust and versatile approach to this problem. Specific and high‐affinity protein‐aptamer binding can nicely interface protein and DNA with structural control. A series of bivalent thrombin aptamers were designed to co‐assemble with thrombin into a range of PDFs including discrete triangles and 3D prisms, linear and circular oligomers, 1D chains/ladders, and 2D arrays. The versatility of such a strategy was further demonstrated by the self‐assembly of Plasmodium falciparum lactate dehydrogenase ( Pf LDH)—containing PDFs. In this work, AlphaFold 3, a universal modeling program, dramatically facilitates structural modeling and helps the designs. We believe that such a rational PDF design will find wide applications as multimodal biomaterials integrating the diverse functionalities of proteins and the ease of assembly programmability of DNA.