Evolutionary computation for predicting optimal reaction knockouts and enzyme modulation strategies

One of the main purposes of Metabolic Engineering is the quantitative prediction of cell behaviour under selected genetic modifications. These methods can then be used to support adequate strain optimization algorithms in a outer layer. The purpose of the present study is to explore methods in which dynamical models provide for phenotype simulation methods, that will be used as a basis for strain optimization algorithms to indicate enzyme under/over expression or deletion of a few reactions as to maximize the production of compounds with industrial interest. This work details the developed optimization algorithms, based on Evolutionary Computation approaches, to enhance the production of a target metabolite by finding an adequate set of reaction deletions or by changing the levels of expression of a set of enzymes. To properly evaluate the strains, the ratio of the flux value associated with the target metabolite divided by the wild-type counterpart was employed as a fitness function. The devised algorithms were applied to the maximization of Serine production by Escherichia coli, using a dynamic kinetic model of the central carbon metabolism. In this case study, the proposed algorithms reached a set of solutions with higher quality, as compared to the ones described in the literature using distinct optimization techniques.This work is funded by National Funds through the FCT - Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) within project PEst-OE/EEI/UI0752/2011. The work is also partially funded by ERDF - European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by National Funds through the FCT within project ref. COMPETE FCOMP-01-0124- FEDER-015079. PEs work is supported by a PhD grant FCT SFRH/BD/51016/2010 from the Portuguese FCT

Improved differential search algorithms for metabolic network optimization

The capabilities of Escherichia coli and Zymomonas mobilis to efficiently converting substrate into valuable metabolites have caught the attention of many industries. However, the production rates of these metabolites are still below the maximum threshold. Over the years, the organism strain design was improvised through the development of metabolic network that eases the process of exploiting and manipulating organism to maximize its growth rate and to maximize metabolites production. Due to the complexity of metabolic networks and multiple objectives, it is difficult to identify near-optimal knockout reactions that can maximize both objectives. This research has developed two improved modelling-optimization methods. The first method introduces a Differential Search Algorithm and Flux Balance Analysis (DSAFBA) to identify knockout reactions that maximize the production rate of desired metabolites. The latter method develops a non-dominated searching DSAFBA (ndsDSAFBA) to investigate the trade-off relationship between production rate and its growth rate by identifying knockout reactions that maximize both objectives. These methods were assessed against three metabolic networks – E.coli core model, iAF1260 and iEM439 for production of succinic acid, acetic acid and ethanol. The results revealed that the improved methods are superior to the other state-of-the-art methods in terms of production rate, growth rate and computation time. The study has demonstrated that the two improved modelling-optimization methods could be used to identify near-optimal knockout reactions that maximize production of desired metabolites as well as the organism’s growth rate within a shorter computation time