ABSTRACT: The ability to design materials that mimic the complexity and functionality of biological systems is a long-standing goal of nanotechnology. Biological molecules such as proteins, peptides, and DNA possess a rich palette of self-assembly motifs and chemical functional diversity, and are attractive building blocks for the synthesis of such nanomaterials. In this chalk talk, I will describe a new direction in my group: using programmable DNA nanostructures as nanoscale “assemblers” (or “molds”, or “3D nano-printers”) to create addressable peptide/protein nanostructures. DNA can be used to create addressable nano-scaffolds with single-molecule precision. Protein and peptide nanotechnology, by contrast, usually yields symmetric assemblies (cages, fibers, sheets, micelles, etc.) due to the paucity of sufficiently orthogonal supramolecular interactions. Even advances in de novo protein design struggle to create more than a handful of unique and selective protein-protein interfaces, let alone tens to hundreds the way that DNA can. We thus asked the question: can we, by tethering polypeptides to addressable DNA handles, position them on a nanostructure with single-molecule precision, and link them into anisotropic polypeptide assemblies not possible with in-solution self-assembly? This requires both selective chemistries to modify these molecules, but also computational methods to design the hybrid assemblies, novel approaches for linking them into the structures, and analysis/application of the final nanostructures created. If successful, however, this “nanostructure-phase synthesis” can yield protein-based nanomaterials and peptide polymers, including, in the blue-sky limit, fully synthetic proteins that far surpass the limitations of the 20 canonical amino acids. Such materials are not possible with current methods, and would open up a wide range of applications in biology, medicine, physics, materials science, and fundamental nanotechnology.
Bio: Nicholas Stephanopoulos was born in Athens, Greece, but grew up outside of Boston, Massachusetts. He obtained his A.B. in chemistry from Harvard University, followed by a Master’s in chemical engineering at MIT. He then pursued doctoral studies at the University of California, Berkeley, working with Prof. Matthew Francis. His research focused on using site-specific bioconjugation chemistry to modify viral capsid nano-scaffolds, in order to create materials for energy, biomedicine, and nanotechnology. After earning his PhD in 2010, he went to Northwestern University for postdoctoral studies, supported by both NIH Ruth Kirschtein and International Institute for Nanotechnology fellowships, working with Prof. Samuel Stupp on self-assembling peptide nanomaterials and their applications to regenerative medicine.
At both Berkeley and Northwestern, Prof. Stephanopoulos became interested in integrating proteins and peptides with DNA nanotechnology. In 2015, he began his independent career at Arizona State University, with a goal to merge these molecules into a new class of hybrid nanomaterials, with applications across a range of fields. He is currently an Associate Professor in the School of Molecular Sciences and the Biodesign Institute’s Center for Molecular Design and Biomimetics, with affiliate appointments in Biomedical Engineering and Chemical Engineering. Since coming to ASU, Prof. Stephanopoulos has received a number of accolades, including the 2016 Air Force (AFOSR) Young Investigator Award, the 2018 NSF CAREER, and the 2018 NIH Director's New Innovator Award. In 2023, he was appointed the Associate Director of the Biodesign Institute’s Center for Molecular Design and Biomimetics.
