CAREER: Higher-order junctions for adaptable and multi-dimensional DNA nanotechnology

NON-TECHNICAL SUMMARY: Our genetic code is made up of DNA, which famously has a double helix structure. This defined structure can be used to form scaffolds and frameworks, like building blocks used in construction. In a way, DNA is a perfect scaffolded material for biotechnology applications because it can be predictably designed so that these building blocks form various geometric shapes. DNA is also inexpensive and non-toxic. Currently, DNA building blocks are somewhat limited in forming 2-D structures. This work will use computational approaches to expand the design and construction of DNA building blocks to enable formation of 3-D structures. The work will result in a platform with programmable and adaptable structures for a wide variety of biotechnological applications such as energy transfer, biomolecular logic, sensing, and therapeutics. In addition to the research effort, the broader impacts of this work will include the training of undergraduate and graduate students, as well as outreach to K-12 students and the public by introducing the concept of DNA structures at a local museum. TECHNICAL SUMMARY: DNA is a biomaterial that can be predictably designed, is relatively inexpensive, easily functionalized, non-toxic, and adaptable, making it an important next-generation biotechnology for various applications, including energy transfer, biomolecular logic, sensing, and therapeutics. These DNA nanomaterials are currently built using a set of building blocks based on the four-way junction (4WJ), where four DNA duplexes are connected, but this architecture is limited by a sparse configurational landscape. Using an expanded set of building blocks based on higher-order DNA junctions, such as the six-way junction (6WJ), this proposal is focused on expanding the design space for DNA nanotechnology. The 6WJ architecture is more structurally complex, consisting of a vast configurational landscape, which allows for multi-dimensional scaffolding of DNA nanotechnology at the junction-level. During the course of this project, this work will (1) map the design space for DNA nanotechnology using the 6WJ architecture which will allow increased lattice precision compared to current technology, (2) learn how to design adaptable or reconfigurable DNA scaffolds with higher-order junctions based on conformational switching, and (3) create software to facilitate design and routing of DNA nanotechnology using higher-order junctions, necessitated by the complexity of the design space. This complex problem requires a bottom-up approach, and this work uses multi-scale molecular modeling techniques including electronic structure predictions, classical molecular dynamics, and AI/ML methods to scan for designs that can be experimentally characterized and confirmed. The properties of DNA nanomaterials built with these junctions could allow for next-generation biotechnology using DNA that approaches the flexibility and adaptability of proteins, while maintaining simplicity of design due to sequence specificity in nucleic acids. In addition to the research effort, the broader impacts of this work will include the training of undergraduate and graduate students, as well as outreach to K-12 students and the public by introducing the concept of DNA nanotechnology at a local museum. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2540375 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT,01002930DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: William Bricker | Institution: University of New Mexico, ALBUQUERQUE, NM | Award Amount: $540,014 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540375 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540375.html