Automated Design of Synthetic Gene Circuits in the Presence of Molecular Noise.

Microorganisms (mainly bacteria and yeast) are frequently used as hosts for genetic constructs in synthetic biology applications. Molecular noise might have a significant effect on the dynamics of gene regulation in microbial cells, mainly attributed to the low copy numbers of mRNA species involved. However, the inclusion of molecular noise in the automated design of biocircuits is not a common practice due to the computational burden linked to the chemical master equation describing the dynamics of stochastic gene regulatory circuits. Here, we address the automated design of synthetic gene circuits under the effect of molecular noise combining a mixed integer nonlinear global optimization method with a partial integro-differential equation model describing the evolution of stochastic gene regulatory systems that approximates very efficiently the chemical master equation. We demonstrate the performance of the proposed methodology through a number of examples of relevance in synthetic biology, including different bimodal stochastic gene switches, robust stochastic oscillators, and circuits capable of achieving biochemical adaptation under noise.