DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression

Yang, Laurence; Ebrahim, Ali; Lloyd, Colton J.; Saunders, Michael A.; Palsson, Bernhard O.

doi:10.1186/s12918-018-0675-6

Title: DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression

Journal Article · 09 January 2019 · BMC Systems Biology

DOI: https://doi.org/10.1186/s12918-018-0675-6 · OSTI ID:1626883

^[1]; Ebrahim, Ali ^[2]; Lloyd, Colton J. ^[2]; Saunders, Michael A. ^[3]; Palsson, Bernhard O. ^[4]

University of California at San Diego, CA (United States). Dept of Bioengineering; DOE/OSTI
University of California at San Diego, CA (United States). Dept of Bioengineering
Stanford Univ., CA (United States). Dept. of Management Science and Engineering
University of California at San Diego, CA (United States). Dept of Bioengineering; Technical University of Denmark (United States). Novo Nordisk Foundation Center for Biosustainability

Background Genome-scale models of metabolism and macromolecular expression (ME models) enable systems-level computation of proteome allocation coupled to metabolic phenotype. Results We develop DynamicME, an algorithm enabling time-course simulation of cell metabolism and protein expression. DynamicME correctly predicted the substrate utilization hierarchy on a mixed carbon substrate medium. We also found good agreement between predicted and measured time-course expression profiles. ME models involve considerably more parameters than metabolic models (M models). We thus generate an ensemble of models (each model having its rate constants perturbed), and then analyze the models by identifying archetypal time-course metabolite concentration profiles. Furthermore, we use a metaheuristic optimization method to calibrate ME model parameters using time-course measurements such as from a (fed-) batch culture. Finally, we show that constraints on protein concentration dynamics (“inertia”) alter the metabolic response to environmental fluctuations, including increased substrate-level phosphorylation and lowered oxidative phosphorylation. Conclusions Overall, DynamicME provides a novel method for understanding proteome allocation and metabolism under complex and transient environments, and to utilize time-course cell culture data for model-based interpretation or model refinement.

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Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1626883

Journal Information:: BMC Systems Biology, Journal Name: BMC Systems Biology Journal Issue: 1 Vol. 13; ISSN 1752-0509

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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Modelling microbial communities using biochemical resource allocation analysis Sharma, Suraj; Steuer, Ralf Journal of The Royal Society Interface, Vol. 16, Issue 160 https://doi.org/10.1098/rsif.2019.0474	journal	November 2019
Computer-Aided Strategies for Determining the Amino Acid Composition of Medium for Chinese Hamster Ovary Cell-Based Biomanufacturing Platforms. Traustason, Bergthor; Cheeks, Matthew; Dikicioglu, Duygu Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.48365	text	January 2019
Computer-Aided Strategies for Determining the Amino Acid Composition of Medium for Chinese Hamster Ovary Cell-Based Biomanufacturing Platforms Traustason, Bergthor; Cheeks, Matthew; Dikicioglu, Duygu International Journal of Molecular Sciences, Vol. 20, Issue 21 https://doi.org/10.3390/ijms20215464	journal	November 2019

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Additional file 1 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570265 The current record is supplemented by this dataset	dataset	January 2019
Additional file 1 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570265.v1 The current record is supplemented by this dataset	dataset	January 2019
Additional file 2 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570271 The current record is supplemented by this text	text	January 2019
Additional file 2 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570271.v1 The current record is supplemented by this text	text	January 2019
Additional file 3 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570277 The current record is supplemented by this text	text	January 2019
Additional file 3 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570277.v1 The current record is supplemented by this text	text	January 2019
Additional file 4 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570289 The current record is supplemented by this text	text	January 2019
Additional file 4 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570289.v1 The current record is supplemented by this text	text	January 2019
Additional file 5 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570295 The current record is supplemented by this dataset	dataset	January 2019
Additional file 5 of DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.7570295.v1 The current record is supplemented by this dataset	dataset	January 2019
DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.c.4361774 The current record is supplemented by this collection	collection	January 2019
DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression Yang, Laurence; Ebrahim, Ali; Lloyd, Colton https://doi.org/10.6084/m9.figshare.c.4361774.v1 The current record is supplemented by this collection	collection	January 2019