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Processes 2019, 7(3), 119; https://doi.org/10.3390/pr7030119

Mechanistic Models of Inducible Synthetic Circuits for Joint Description of DNA Copy Number, Regulatory Protein Level, and Cell Load

1
Laboratory of Bioinformatics, Mathematical Modelling and Synthetic Biology, Department of Electrical, Computer and Biomedical Engineering, University of Pavia, I-27100 Pavia, Italy
2
Centre for Health Technologies, University of Pavia, I-27100 Pavia, Italy
*
Author to whom correspondence should be addressed.
Received: 14 December 2018 / Revised: 5 February 2019 / Accepted: 19 February 2019 / Published: 26 February 2019
(This article belongs to the Special Issue Computational Synthetic Biology)
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Abstract

Accurate predictive mathematical models are urgently needed in synthetic biology to support the bottom-up design of complex biological systems, minimizing trial-and-error approaches. The majority of models used so far adopt empirical Hill functions to describe activation and repression in exogenously-controlled inducible promoter systems. However, such equations may be poorly predictive in practical situations that are typical in bottom-up design, including changes in promoter copy number, regulatory protein level, and cell load. In this work, we derived novel mechanistic steady-state models of the lux inducible system, used as case study, relying on different assumptions on regulatory protein (LuxR) and cognate promoter (Plux) concentrations, inducer-protein complex formation, and resource usage limitation. We demonstrated that a change in the considered model assumptions can significantly affect circuit output, and preliminary experimental data are in accordance with the simulated activation curves. We finally showed that the models are identifiable a priori (in the analytically tractable cases) and a posteriori, and we determined the specific experiments needed to parametrize them. Although a larger-scale experimental validation is required, in the future the reported models may support synthetic circuits output prediction in practical situations with unprecedented details. View Full-Text
Keywords: mathematical modeling; mechanistic model; synthetic biology; copy number; inducible promoter; cell load; bottom-up design mathematical modeling; mechanistic model; synthetic biology; copy number; inducible promoter; cell load; bottom-up design
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Pasotti, L.; Bellato, M.; De Marchi, D.; Magni, P. Mechanistic Models of Inducible Synthetic Circuits for Joint Description of DNA Copy Number, Regulatory Protein Level, and Cell Load. Processes 2019, 7, 119.

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