title: Pareto Optimal Design for Synthetic Biology.
abstract: Recent advances in synthetic biology call for robust, flexible and efficient in silico optimization methodologies. We present a Pareto design approach for the bi-level optimization problem associated to the overproduction of specific metabolites in Escherichia coli. Our method efficiently explores the high dimensional genetic manipulation space, finding a number of trade-offs between synthetic and biological objectives, hence furnishing a deeper biological insight to the addressed problem and important results for industrial purposes. We demonstrate the computational capabilities of our Pareto-oriented approach comparing it with state-of-the-art heuristics in the overproduction problems of i) 1,4-butanediol, ii) myristoyl-CoA, i ii) malonyl-CoA , iv) acetate and v) succinate. We show that our algorithms are able to gracefully adapt and scale to more complex models and more biologically-relevant simulations of the genetic manipulations allowed. The Results obtained for 1,4-butanediol overproduction significantly outperform results previously obtained, in terms of 1,4-butanediol to biomass formation ratio and knock-out costs. In particular overproduction percentage is of +662.7%, from 1.425 mmolh⁻¹gDW⁻¹ (wild type) to 10.869 mmolh⁻¹gDW⁻¹, with a knockout cost of 6. Whereas, Pareto-optimal designs we have found in fatty acid optimizations strictly dominate the ones obtained by the other methodologies, e.g., biomass and myristoyl-CoA exportation improvement of +21.43% (0.17 h⁻¹) and +5.19% (1.62 mmolh⁻¹gDW⁻¹), respectively. Furthermore CPU time required by our heuristic approach is more than halved. Finally we implement pathway oriented sensitivity analysis, epsilon-dominance analysis and robustness analysis to enhance our biological understanding of the problem and to improve the optimization algorithm capabilities.
authors.forename: Andrea
authors.initials: A
authors.lastname: Patanè
authors.forename: Andrea
authors.initials: A
authors.lastname: Santoro
authors.forename: Jole
authors.initials: J
authors.lastname: Costanza
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carapezza
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nicosia
mesh_terms: D000085:Acetates / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D002072:Butylene Glycols / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008954:Models, Biological; D019802:Succinic Acid / Q000378:metabolism; D058615:Synthetic Biology / Q000379:methods
chemical_list: D000085:Acetates; D000214:Acyl Coenzyme A; D002072:Butylene Glycols; D005227:Fatty Acids; C040349:S-tetradecanoyl-coenzyme A; D008316:Malonyl Coenzyme A; C039681:1,4-butanediol; D019802:Succinic Acid