Hierarchical Assembly of Protein-DNA and Peptide-DNA Nanomaterials

Nature is full of hierarchically-structured nanomaterials based on proteins, and scientists have long been interested in recapitulating this complexity to create functional bio/nanomaterials. However, it is still challenging to create protein-based nanomaterials, especially if a high degree of asymmetry and heterogeneity is desired, due to the difficulty of engineering multiple, sufficiently orthogonal interfaces into proteins. Although de novo protein design has made impressive strides in creating novel self-assembled protein nanostructures, it is still largely confined to highly symmetric structures like cages, nanofibers, or sheets. DNA nanotechnology, by contrast, relies on the self-assembly of hundreds or even thousands of unique oligonucleotides due to the exquisite orthogonality of the Watson-Crick code, and can generate highly complex and addressable nanostructures with arbitrarily complex shapes, sizes, and curvature. These are, however, for the most part limited to the structural and chemical properties of DNA, and cannot recapitulate the broad functions of proteins. In this talk, I will describe our work on merging the structural programmability of DNA nanotechnology with the chemical and functional diversity of peptides and proteins, through the use of site-specific polypeptide-DNA hybrid molecules. I will describe the synthesis of peptide-DNA and protein-DNA bioconjugates, and describe our recent advances in modifying these molecules with two oligonucleotide strands in an efficient and site-specific fashion. These molecules have been used in the hierarchical assembly of protein-DNA nanocages and peptide-DNA nanofibers, which have exciting applications in targeted therapeutic delivery and functional biomaterials. Finally, I will describe our ongoing efforts to use DNA nanoscaffolds in two exciting directions: (1) synthesizing sequence-defined polypeptides, linked by both native amide bonds and non-native chemical linkages; and (2) building anisotropic protein-based nanostructures that are not possible through direct protein self-assembly alone. Taken together, our work showcases the potential for using DNA as both an addressable linker and as a nanoscale “assembler” to create polypeptide-based molecules and materials with exciting applications in nanotechnology, biology, medicine, and materials science.