SURF 2012: Biomolecular rate-regulator circuits

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2012 SURF project description

  • Mentor: Richard Murray
  • Co-mentor: Elisa Franco (UC Riverside)

Flux control is a fundamental feature for the correct performance of biochemical systems. Mechanisms of production rate and concentration regulation are important when a large number of metabolites operate according to specific stoichiometric interactions. A simple case is given by flux regulation of two molecules that bind with one to one stoichiometry to form an output product. Self repression feedback loops can be used to minimize the amount of molecules not used to form the product, while cross activation maximizes the overall output flux. This system has been studied and demonstrated using in vitro artificial gene circuits, and we are interested in developing and generalizing this kind of circuitry. These regulatory schemes could be useful when large synthetic pathways are integrated into a host: minimization of the translation burden of unnecessary enzymes (negative feedback) may be necessary for survival of the host; maximization the output of the pathway (positive feedback) might be essential to guarantee yield of specific metabolites.

Research directions for a SURF project include:

  • Generalize and scale up flux regulation circuitry to an arbitrary number of metabolites, using positive or negative feedback
  • Design synthetic gene circuits that implement alternative signaling regulation pathways as a function of the output product. For example, devise methods to separate feedback and production chemical signals, matching their value with known gains. This is particularly important if the final output product is given by a protein complex.
  • Compare the performance of feedback generated with second order kinetics and Hill functions, for the purpose of matching the transcription rate of two or more genetic circuits.

We are interested in both theoretical/computational and experimental work on this topic.

References:

  1. E. Franco, P. O. Forsberg and R. M. Murray. Design, modeling and synthesis of an in vitro transcription rate regulatory circuit. American Control Conference, 2008.
  2. E. Franco and R. M. Murray. Design and performance of in vitro transcription rate regulatory circuit. Conference on Decision and Control (CDC), 2008.
  3. E. Franco. Analysis, design, and in vitro implementation of robust biochemical networks. PhD Thesis, Caltech, 2011.
  4. J. Kim, K. S. White and E. Winfree. Construction of an in vitro bistable circuit from synthetic transcriptional switches. Molecular Systems Biology, 2:68, 2006