Control of molecular structure and reactivity at the nanometer scale has been a dream of chemists for years. For far longer, Nature has accomplished this feat with immense variation and scale, relying on bottom-up self-assembly of genetically evolved components to build structures and reaction pathways far more complex than anything humans can design. Nucleic acid nanotechnology has emerged as an exciting field in which the programmable hybridization rules of Watson-Crick base pairing are used to construct intricate two- and three-dimensional structures, carry out logic operations, and build molecular circuits and motors that operate at the smallest of scales. The theme of my proposed research is to leverage the advances of nucleic acid nanotechnology to build functional nano-devices capable of carrying out chemical transformations and probing biochemical systems in vitro and in vivo. Programming chemical reactivity I have recently developed new methods to form site-specific covalent linkages between oligonucleotides and proteins, and plan to use these to design enzymatic cascades in which the product of one reaction immediately becomes the substrate of another, avoiding the need for high intermediate concentrations. Additionally, I will continue a collaboration developing nucleic acids as conformationally-controllable ligands for organometallic catalysis. Biomolecular phase transitions In both membraneless organelles and pathological aggregates, molecular conformation change drives phase separation in vivo. We recently found that the phase of nucleic acid-peptide complexes is controlled by nucleic acid hybridization. I plan to extend this work to full-length mRNA and proteins in order to determine the physical principles governing phase transitions in normal and pathological states. The same principles will enable the design of nanoparticles for more efficient delivery of therapeutic nucleic acids, a key challenge to realizing the potential of therapies such as siRNA. Nucleic acid nanotechnology in vivo Despite their inherent biocompatibility and therapeutic potential, the vast majority of nucleic acid nanodevices function only in test tubes. Building upon the outcomes of the above projects, as well as studies I am currently pursuing on the effect of crowding on strand displacement dynamics, I plan to develop nucleic acid nanodevices capable of sensing genetic state and producing therapeutic products when and where they are needed, in living organisms.

Programming self-assembly and function at multiple scales with nucleic acids

254th National Meeting (2017)

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