Abstract
Chemical space exploration is an important part of chemistry and biology, enabling the discovery and optimization of metabolic pathways, advancing synthetic metabolic functions, and understanding biochemical network evolution. We use a graph-based computational approach implemented in the cheminformatics software MØD, integrated with Integer Linear Programming (ILP) optimization, to systematically search chemical spaces. This approach allows for flexible and targeted queries, including identification of autocatalytic cycles, thermodynamic considerations, and discovery of novel enzymatic cascades. Specifically, we explore the chemical space of natural and artificial carbon fixation pathways defined from relevant enzyme reactions. By applying different optimization criteria, we identify new varieties and recombinations of natural autocatalytic pathways, and compare the properties of the pathways. This work highlights the versatility of graph-based cheminformatics for the purpose of chemical space exploration and artificial pathway design. Potential applications of this framework extend to carbon capture technologies, improved agricultural yields, and value-added chemical production, advancing efforts to address global sustainability challenges.
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Data availability
The datasets generated and analyzed during the current study, as well as the underlying code are available in the GitHub repository https://github.com/anne-susann/C_fixation_pathway_design.
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Acknowledgements
We thank Prof. Annette Taylor (University of South Hampton) for scientific discussions and her input on the manuscript. This project was funded by the European Unions Horizon Europe Doctoral Network program under the Marie-Skłodowska-Curie grant agreement No 101072930 (TACsy - Training Alliance for Computational systems chemistry). The funder played no role in study design, analysis, and interpretation of the data.
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C.F., R.F., J.L.A., D.M. conceptualized and supervised the study. J.L.A., N.L., and C.F. provided the computational framework, and with A-S.A. they designed the set-up and experiments. A-S.A. implemented and performed the computational experiments, the data analysis, and the writing and editing of the paper. C.F., R.F., J.L.A., and D.M. revised and with N.L. edited the manuscript.
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Abel, AS., Lauber, N., Andersen, J.L. et al. Computational approaches in chemical space exploration for carbon fixation pathways. npj Syst Biol Appl (2026). https://doi.org/10.1038/s41540-025-00641-8
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DOI: https://doi.org/10.1038/s41540-025-00641-8
