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Additional file 1 Additional text, boxes, and tables. Text. Descriptions of the grammars, coordinate system, construction of the alphabets of residues and the ontology of crosslinks, semantic verification, user interfaces, and implementation; comparisons with other resources; glossary; and acronyms. Box S1. Integration of BpForms with the FASTA format to describe multiple polymers within a single document. Box S2. Integration of BpForms with BioPAX documents to describe the polymers involved in pathways. Box S3. Integration of BpForms with SBML to describe the semantic meaning of the macromolecules represented by models. Box S4. Integration of BpForms with CellML to describe the semantic meaning of components which represent macromolecules. Box S5. Integration of BpForms with SBOL to describe DNA, RNA, and protein parts. Box S6. Tutorial for the BpForms command line program. Box S7. Tutorial for the BcForms command line program. Box S8. Tutorial for the BpForms Python library. Box S9. Tutorial for the BcForms Python library. Table S1. Comparison between BpForms and other formats for describing polymers. Table S2. Comparison between BpForms and other collections of DNA, RNA, and protein residues. Table S3. Comparison between the BpForms crosslinks ontology and other resources that describe crosslinks. Table S4. Comparison between BcForms and other formats for describing complexes. Table S5. The most common constraints on transforming proteins into E. coli due to missing post-translational machinery learned from the PDB with BpForms. Most of the information in Additional file 1 is also in the online user and developer tutorials and documentations at https://bpforms.org, https://bcforms.org, https://sandbox.karrlab.org,and\url{https://docs.karrlab.org}.

Additional file 2 Review history.

Whole-cell (WC) models that predict phenotype from genotype have the potential to transform biology, bioengineering, and medicine. Achieving WC models will likely require collaboration among modelers, experimentalists, mathematicians, computer scientists, and engineers. In 2012, we and others began to build a WC community by organizing a central website, a primer, schools, hackathons, and challenges. This year, we have continued to build a WC community by developing a new website, expanding the primer, organizing a third school, and launching an online seminar. Here, we summarize these initiatives, their impact to date, and our plans to continue to build a WC community.

Whole-cell models that predict phenotype from genotype are needed to advance biology, bioengineering, and medicine. Achieving whole-cell models will require extensive collaboration among modelers, experimentalists, mathematicians, computer scientists, and software engineers. In September2017, we organized the second Whole-Cell Modeling Summer School to continue to build a whole-cell community by training new researchers. The school created new whole-cell training materials;trained 18 students, postdoctoral scholars, and faculty; and generated ideas about how to better teach whole-cell modeling. To build a whole-cell modeling community, we plan to continue to organize schools, continue to improve these schools based on the lessons that we learned this year, andinitiate an annual workshop and/or online seminar series to facilitate sustained discussion aboutwhole-cell modeling.

Whole-cell models predict cell behaviors by modeling all molecular components and their interactions. Recently, we and other developed the first whole-cell model. The model represents the functionality of all 409 characterized genes and 725 metabolites throughout one life cycle of the reduced bacterium Mycoplasma genitalium. This model was validated against a broad range of data and provided insights into many previously unobserved cellular behaviors. Simulating the behavior of a single cell required modest computing resources – 1 core-day of an Intel E5520 CPU, capable of 3.3×1015 double-precision floating-point operations during the computation. Sampling the organism’s behavior required 128 simulations. Nevertheless, we anticipate that exascale computing resources will be required to use more comprehensive and more accurate whole-cell models to personalize medicine and engineer bacteria.

Whole-cell (WC) models that predict phenotype from genotype have the potential to transform biology, bioengineering, and medicine. Achieving WC models will likely require collaboration among modelers, experimentalists, mathematicians, computer scientists, and engineers. In 2012, we and others began to build a WC community by organizing a central website, a primer, schools, hackathons, and challenges. This year, we have continued to build a WC community by developing a new website, expanding the primer, organizing a third school, and launching an online seminar. Here, we summarize these initiatives, their impact to date, and our plans to continue to build a WC community., These efforts were supported by National Science Foundation awards 1548123 and 1649014 to JRK, National Institutes of Health award R35 GM119771 to JRK, and National Institutes of Health award P41 EB023912 to Herbert Sauro. The 2019 school was also supported by an EMBO Practical Course award to JRK, MLS, and DK., {"references":["Tomita, M. Whole-cell simulation: a grand challenge of the 21st century. Trends Biotechnol 19, 205–210 (2001).","Karr, J. R., Takahashi, K. & Funahashi, A. The principles of whole-cell modeling. Curr Opin Microbiol 27, 18–24 (2015).","Carrera, J. & Covert, M. W. Why build whole-cell models? Trends Cell Biol 25, 719–722 (2015).","Karr, J. R. et al. A whole-cell computational model predicts phenotype from genotype. Cell 150, 389–401 (2012).","Macklin, D. N., Ruggero, N. A. & Covert, M. W. The future of whole-cell modeling. Curr Opin Biotechnol 28, 111–115 (2014).","Goldberg, A. P. et al. Emerging whole-cell modeling principles and methods. Curr Opin Biotechnol 51, 97–102 (2018).","Szigeti, B. et al. A blueprint for human whole-cell modeling. Curr Opin Syst Biol 7, 8–15 (2018).","Karr, J. R. & Pochiraju, S. Whole-cell modeling https://www.wholecell.org (2019).","Karr, J. R. et al. Summary of the DREAM8 parameter estimation challenge: toward parameter identification for whole-cell models. PLoS Comput Biol 11, e1004096 (2015).","Hucka, M. et al. The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19, 524–531 (2003).","Waltemath, D. et al. Toward community standards and software for whole-cell modeling. IEEE Trans Biomed Eng 63, 2007–2014 (2016).","Karr, J. R., Lluch-Senar, M, Serrano, L & Carrera, J. The 2016 Whole-Cell Modeling Summer School https://doi.org/10.5281/zenodo.1004027 (2016).","Karr, J. R., Lluch-Senar, M, Serrano, L & Carrera, J. The 2017 Whole-Cell Modeling Summer School https://doi.org/10.5281/zenodo.1004135 (2017).","Karr, J. R. & Goldberg, A. P. An introduction to whole-cell modeling https://intro-to- wc-modeling.readthedocs.io (2017).","Karr, J. R., Lluch-Senar, M, Kastelic, D & Serrano, L. 2019 EMBO whole-cell modeling sum- mer school http://meetings.embo.org/event/19-whole-cell-modelling (2019).","Roth, Y. D., Porubsky, V., Sauro, H. M. & Karr, J. R. Online whole-Cell modeling seminar https://reproduciblebiomodels.org/seminar (2019).","Medley, J. K., Goldberg, A. P. & Karr, J. R. Guidelines for reproducibly building and simu- lating systems biology models. IEEE Trans Biomed Eng 63, 2015–2020 (2016).","Watanabe, L., König, M. & Myers, C. Dynamic flux balance analysis models in SBML. BioRXiv, 245076 (2018).","Burke, P. E., de Campos, C. B. & Quiles, M. G. Whole-cell representation and analysis of My- coplasma genitalium organism using complex networks. ComplexNet. doi: 10.13140/2.1.3736.6084.","Rees, J. et al. Designing minimal genomes using whole-cell models. bioRxiv, 344564 (2019)."]}

Whole-cell models that predict phenotype from genotype are needed to advance biology, bioengineering, and medicine. Achieving whole-cell models will require extensive collaboration among modelers, experimentalists, mathematicians, computer scientists, and software engineers. In September 2017, we organized the second Whole-Cell Modeling Summer School to continue to build a whole-cell community by training new researchers. The school created new whole-cell training materials; trained 18 students, postdoctoral scholars, and faculty; and generated ideas about how to better teach whole-cell modeling. To build a whole-cell modeling community, we plan to continue to organize schools, continue to improve these schools based on the lessons that we learned this year, and initiate an annual workshop and/or online seminar series to facilitate sustained discussion about whole-cell modeling., The school was partly supported by ERASynBio award to JRK, LS, and MLS; Horizon 2020 award 634942 to LS; and National Science Foundation award 1649014 to JRK., {"references":["Tomita, M. Whole-cell simulation: a grand challenge of the 21st century. Trends Biotechnol 19, 205–210 (2001).","Karr, J. R., Takahashi, K. & Funahashi, A. The principles of whole-cell modeling. Curr Opin Microbiol 27, 18–24 (2015).","Carrera, J. & Covert, M. W. Why build whole-cell models? Trends Cell Biol 25, 719–722 (2015).","Karr, J. R. et al. A whole-cell computational model predicts phenotype from genotype. Cell 150, 389–401 (2012).","Macklin, D. N., Ruggero, N. A. & Covert, M. W. The future of whole-cell modeling. Curr Opin Biotechnol 28, 111–115 (2014).","Goldberg, A. P. et al. Emerging whole-cell modeling principles and methods. Curr Opin Biotechnol (In submission).","Szigeti, B et al. A blueprint for human whole-cell modeling. Curr Opin Syst Biol (In submis- sion).","Karr, J. R., Lluch-Senar, M, Serrano, L & Carrera, J. The 2016 Whole-Cell Modeling Summer School http://www.karrlab.org/static/doc/papers/Karr2016.pdf (2016).","Waltemath, D. et al. Toward community standards and software for whole-cell modeling. IEEE Trans Biomed Eng 63, 2007–2014 (2016).","Karr, J. R., Lluch-Senar, M, Serrano, L & Kastelic, D. 2017 Whole-Cell Modeling Summer School http://www.wholecell.org/school-2017 (2017).","Karr, J. R. & Goldberg, A. P. An introduction to whole-cell modeling http://intro-to-wc- modeling.readthedocs.io (2017).","European Molecular Biology Organization. Practical course funding http://www.embo.org/ funding-awards/courses-workshops/practical-courses (2017)."]}

Whole-cell models that predict phenotype from genotype are needed to advance biology, bioengineering, and medicine. Achieving whole-cell models will require extensive collaboration among modelers, experimentalists, mathematicians, computer scientists, and software engineers. In April 2016, we organized the first Whole-Cell Modeling Summer School to begin to build a whole-cell community by training new researchers. The school created the first whole-cell training materials; trained 21 graduate students, postdoctoral scholars, and faculty; and generated ideas about how to better teach whole-cell modeling. To build a whole-cell modeling community, we plan to continue to organize schools, continue to improve these schools based on the lessons that we learned this year, and initiate an annual workshop and/or online seminar series to facilitate sustained discussion about whole-cell modeling.