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This 2-input 2-output platform can implement 256 different logical circuits that exploit the specificity and stability of DNA recombination. Here, we develop the first mechanistic mathematical model of the 2-input BLADE platform based on Cre- and Flp-mediated DNA excision. After calibrating the model on experimental data from two circuits, we demonstrate close agreement between model outputs and data on the other 111 circuits that have so far been experimentally constructed using the 2-input BLADE platform. Model simulations of the remaining 143 circuits that have yet to be tested experimentally predict excellent performance of the 2-input BLADE platform across the range of possible circuits. Circuits from both the tested and untested subsets that perform less well consist of a disproportionally high number of STOP sequences. Model predictions suggested that circuit performance declines with a decrease in recombinase expression and new experimental data was generated that confirms this relationship.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1007849","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T14:32:37Z","timestamp":1608301957000},"page":"e1007849","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["A mechanistic model of the BLADE platform predicts performance characteristics of 256 different synthetic DNA recombination circuits"],"prefix":"10.1371","volume":"16","author":[{"given":"Jack E.","family":"Bowyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7277-5081","authenticated-orcid":true,"given":"Chloe","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2604-2260","authenticated-orcid":true,"given":"Benjamin H.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-889X","authenticated-orcid":true,"given":"Wilson W.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1395-9846","authenticated-orcid":true,"given":"Declan G.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"pcbi.1007849.ref001","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/35002125","article-title":"A synthetic oscillatory network of transcriptional regulators","volume":"403","author":"MB Elowitz","year":"2000","journal-title":"Nature"},{"key":"pcbi.1007849.ref002","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/35002131","article-title":"Construction of a genetic toggle switch in Escherichia coli","volume":"403","author":"TS Gardner","year":"2000","journal-title":"Nature"},{"key":"pcbi.1007849.ref003","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nrm2698","article-title":"The second wave of synthetic biology: from modules to systems","volume":"10","author":"PEM Purnick","year":"2009","journal-title":"Nat. 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