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Such enzymatic function was linked to RNA sequences capable of adopting specific RNA folds that possess catalytic pockets to promote catalysis. Within this primordial RNA world, initially evolved self\u2010replicating ribozymes presumably mutated to ribozymes with new functions. Schultes and Bartel (<jats:italic>Science<\/jats:italic> <jats:bold>2000<\/jats:bold>, <jats:italic>289<\/jats:italic>, 448\u2013452) investigated such conversion from one ribozyme to a new ribozyme with distinctly different catalytic functions. Within a neutral network that linked these two prototype ribozymes, a single RNA chain could be identified that exhibited both enzymatic functions. As commented by Schultes and Bartel, this system possessing one sequence with two enzymatic functions serves as a paradigm for an evolutionary system that allows neutral drifts by stepwise mutation from one ribozyme into a different ribozyme without loss of intermittent function. Here, we investigated this complex functional diversification of ancestral ribozymes by analyzing several RNA sequences within this neutral network between two ribozymes with class III ligase activity and with self\u2010cleavage reactivity. We utilized rapid RNA sample preparation for NMR spectroscopic studies together with SHAPE analysis and in\u2010line probing to characterize secondary structure changes within the neutral network. Our investigations allowed delineation of the secondary structure space and by comparison with the previously determined catalytic function allowed correlation of the structure\u2010function relation of ribozyme function in this neutral network.<\/jats:p>","DOI":"10.1002\/cbic.202200022","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T05:39:36Z","timestamp":1643866776000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mapping the Conformational Landscape of the Neutral Network of RNA Sequences That Connect Two Functional Distinctly Different Ribozymes"],"prefix":"10.1002","volume":"23","author":[{"given":"Bozana","family":"Knezic","sequence":"first","affiliation":[{"name":"Institute for Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance (BMRZ) Johann Wolfgang Goethe University  Max-von-Laue-Str. 7 60438 Frankfurt\/Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Keyhani\u2010Goldau","sequence":"additional","affiliation":[{"name":"Institute for Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance (BMRZ) Johann Wolfgang Goethe University  Max-von-Laue-Str. 7 60438 Frankfurt\/Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5693-7909","authenticated-orcid":false,"given":"Harald","family":"Schwalbe","sequence":"additional","affiliation":[{"name":"Institute for Organic Chemistry and Chemical Biology Center for Biomolecular Magnetic Resonance (BMRZ) Johann Wolfgang Goethe University  Max-von-Laue-Str. 7 60438 Frankfurt\/Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/319618a0"},{"volume-title":"The RNA World","year":"1999","author":"Gestland R. 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