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Start of funding 01.07.2012

Programming dynamic growth of nucleic acid structures through biochemical signaling: a step toward the design and synthesis of reconfigurable bio-materials

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The collaboration between the Franco lab at UC Riverside and the Simmel lab at TU München aims at the realization of synthetic computational molecular circuits that control the assembly of nucleic acid based nanostructures. In the past, DNA molecules have been shown to be exquisite components for the construction of molecular nanostructures. Furthermore, DNA molecules have been used to realize molecular circuits that can perform logical functions, or display interesting dynamical behavior such as bistability or oscillations. These aspects of artificial DNA-based molecular systems will be brought together by using DNA-based circuits for the spatiotemporal control of the assembly pathways of DNA nanostructures. Among other goals, we aim at the control of assembly and disassembly reaction of DNA-based supramolecular structures in response to environmental cues, similar to dynamic biological assembly reactions taking place in live cells.

Final report:
Living cells grow, divide, and adapt their shape to the environment thanks to flexible, responsive and self-assembling structural scaffolds collectively known as the cytoskeleton. Taking inspiration from nature, this BaCaTec project aimed at establishing novel design principles and methodologies to build responsive nucleic acid scaffolds that can be controlled by molecular cues, which could be useful for manifold applications in synthetic biology, materials science, and artificial life. Nucleic acids are an ideal biomolecular material to undertake this effort, because the interactions between DNA and RNA molecules are rationally programmable by designing their sequence content. For this purpose, we established a collaboration between UC Riverside (Franco) and the Technical University of Munich (Simmel). BaCaTec funding supported two graduate students (Leopold Green and Maximilian Weitz) for research exchanges between UCR and TUM. These visits enabled the development of experimental protocols, modeling techniques, and design methods to a) encapsulate complex molecular circuits in droplets, which may have the function of timers and pattern generators within artificial cells [1,2]; b) tune molecular oscillators to obtain predictable period and amplitude [3]; c) build DNA nanotubes whose assembly and disassembly can be controlled by DNA or RNA inputs, pH, and molecular circuits [4,5]. The next steps of the project include 1) the encapsulation of both DNA scaffolds and circuits within droplet systems and vesicles to build mechanically responsive cell-like compartments, and 2) the establishment of inter-compartment communication to generate patterns based on scaffold responses, mimicking biological developmental phenomena.
Refs. [1] & [3] were immediate consequences of the collaboration, the other publications resulted from the ideas developed during the funding period.

[1] Weitz, M., Kim, J., Kapsner, K., Winfree, E., Franco, E., & Simmel, F. C. (2014). Diversity in the dynamical behaviour of a compartmentalized programmable biochemical oscillator. Nature Chemistry, 6(4), 295-302.
[2] Dupin, A. and Simmel, F.C., 2019. Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits. Nature Chemistry, 11(1), 32-39.
[3] Schwarz-Schilling, M., Kim, J., Cuba, C., Weitz, M., Franco, E., & Simmel, F. C. (2016). Building a Synthetic Transcriptional Oscillator. In Cell Cycle Oscillators (pp. 185-199). Humana Press, New York, NY.
[4] Green, L.N., Amodio, A., Subramanian, H.K., Ricci, F. and Franco, E., 2017. pH-driven reversible self-assembly of micron-scale DNA scaffolds. Nano Letters, 17(12), 7283-7288.
[5] Green, L.N., Subramanian, H.K., Mardanlou, V., Kim, J., Hariadi, R.F., and Franco, E., 2019. Autonomous control of DNA nanostructure self-assembly. Nature Chemistry, 11(1), in press.