{"about":{"site":"https://codewithpapers.app","non_affiliation":"Code with Papers and Syntology are not affiliated with, endorsed by, or sponsored by Papers with Code, Meta, or the pwc-archive mirror.","licence":"CC BY-SA 4.0","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","attribution":"https://codewithpapers.app/attribution","modified":"archive material modified by Syntology; see the attribution page"},"url":"/paper/the-energetics-of-molecular-adaptation-in","title":"The Energetics of Molecular Adaptation in Transcriptional Regulation","arxiv_id":"1905.06360","date":"2019-05-15","proceeding":null,"authors":[],"abstract":"Mutation is a critical mechanism by which evolution explores the functional\nlandscape of proteins. Despite our ability to experimentally inflict mutations\nat will, it remains difficult to link sequence-level perturbations to\nsystems-level responses. Here, we present a framework centered on measuring\nchanges in the free energy of the system to link individual mutations in an\nallosteric transcriptional repressor to the parameters which govern its\nresponse. We find the energetic effects of the mutations can be categorized\ninto several classes which have characteristic curves as a function of the\ninducer concentration. We experimentally test these diagnostic predictions\nusing the well-characterized LacI repressor of Escherichia coli, probing\nseveral mutations in the DNA binding and inducer binding domains. We find that\nthe change in gene expression due to a point mutation can be captured by\nmodifying only a subset of the model parameters that describe the respective\ndomain of the wild-type protein. These parameters appear to be insulated, with\nmutations in the DNA binding domain altering only the DNA affinity and those in\nthe inducer binding domain altering only the allosteric parameters. Changing\nthese subsets of parameters tunes the free energy of the system in a way that\nis concordant with theoretical expectations. Finally, we show that the\ninduction profiles and resulting free energies associated with pairwise double\nmutants can be predicted with quantitative accuracy given knowledge of the\nsingle mutants, providing an avenue for identifying and quantifying epistatic\ninteractions.","url_abs":"http://arxiv.org/abs/1905.06360v1","url_pdf":"http://arxiv.org/pdf/1905.06360v1.pdf","source":{"archive":"pwc-archive (Hugging Face), CC BY-SA 4.0","snapshot":"2025-07-28","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","row_kind":"abstracts"},"code_links":[{"paper_slug":"the-energetics-of-molecular-adaptation-in","repo_url":"https://github.com/rpgroup-pboc/mwc_mutants","is_official":1,"mentioned_in_paper":1,"mentioned_in_github":0,"framework":"none","reach":null}],"tasks":[{"task_slug":"diagnostic","task_name":"Diagnostic"}],"methods":[],"datasets_introduced":[],"methods_introduced":[],"results":[],"syntology":{"syntology_url":null,"atlas_url":null,"mcp":null,"developers":"https://syntology.ai/developers"},"arxiv_metadata":null,"syntology_extracted_results":null}