PT  - JOURNAL ARTICLE
AU  - Wheaton L. Schroeder
AU  - Rajib Saha
TI  - A Novel Optimization-Based Tool to Automate Infeasible Cycle-Free Gapfilling of Genome-Scale Metabolic Models
AID  - 10.1101/796706
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 796706
4099  - http://biorxiv.org/content/early/2019/10/07/796706.short
4100  - http://biorxiv.org/content/early/2019/10/07/796706.full
AB  - Stoichiometric metabolic modeling, particularly Genome-Scale Models (GSMs), is now an indispensable tool for systems biology. The model reconstruction process typically involves collecting information from public databases; however, incomplete systems knowledge leaves gaps in any reconstruction. Current tools for addressing gaps use databases of biochemical functionalities to address gaps on a per-metabolite basis and can provide multiple solutions, but cannot avoid Thermodynamically Infeasible Cycles (TICs), invariably requiring lengthy manual curation. To address these limitations, this work introduces an optimization-based multi-step method named OptFill which performs TIC-avoiding whole-model gapfilling. We applied OptFill to three fictional prokaryotic models of increasing sizes and to a published GSM of Escherichia coli, iJR904. This application resulted in holistic and infeasible cycle free gapfilling solutions. Part of OptFill can, in addition, be adapted to automate inherent TICs identification in any GSM, such as iJR904. Overall, OptFill can address critical issues in automated development of high-quality GSMs.In Brief Stoichiometric models of metabolism are useful in studying metabolic interactions in biological systems, but are labor-intensive to create, particularly when addressing gaps or cycles in metabolic reconstruction process. Introduced here is a novel tool, OptFill, which can be used to address both gaps and cycles in model reconstruction, increasing automation.HighlightsThis work presents an alternative to state-of-the-art methods for gapfilling.Unlike current methods, this method is holistic and infeasible cycle free.This method is applied to three test and one published model.This method might also be used to address infeasible cycling.LHSLeft Hand SideRHSRight Hand SideTFPTIC-Finding ProblemCPsConnecting ProblemsFBAFlux Balance AnalysisTM1First Test ModelTDb1First Test DatabaseTM2Second Test ModelTDb2First Test DatabaseTM3Third Test ModelTDb3First Test DatabaseGAMGrowth Associated MaintenanceNGAMNon-Growth Associated Maintenance