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Helical bundles were observed with high frequency when insertions or deletions were included between blocks of repeating sequences. We also observed a new supersecondary structure consisting of a tightly wound \u03b1-helical screw and experimentally confirmed its stability and structure by circular dichroism (CD) spectroscopy and X-ray crystallography. Thus, structure predictors can discover structures that are well out of the distribution of the data upon which they were trained. Beyond 40-residue repeat lengths, very few sequences were predicted to fold. The small number of structures we observed was representative of well-established major classes of tertiary structures; greater sampling would be needed to discover novel structures from a random distribution. These studies illuminate dark matter regions of protein structure space and support previous predictions that proteins evolved through the assortment of shorter peptide sequences.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2535076123","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T19:11:41Z","timestamp":1782760301000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["The emergence of novel versus known three-dimensional structures from random sequences"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2534-0242","authenticated-orcid":false,"given":"Rose","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2524-2201","authenticated-orcid":false,"given":"Hyunjun","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, Brandeis University","place":["Waltham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Davydenko","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, Brandeis University","place":["Waltham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zack","family":"Mawaldi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rian","family":"Kormos","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dru","family":"Myerscough","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-263X","authenticated-orcid":false,"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California San Francisco","place":["San Francisco"]},{"id":[{"id":"https:\/\/ror.org\/01dq60k83","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Multidisciplinary Research for Advanced Materials, Tohoku University","place":["Sendai, Miyagi, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"22","volume-title":"M\u00f6ssbauer Spectroscopy in Biological Systems, Proceedings of a meeting held at Allerton House, Monticello, IL","author":"Levinthal C.","year":"1969","unstructured":"C. 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