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In this study, we investigated 664 candidate novel fold (CNF) domains from the TED database that both TED and DPAM methods had classified with low confidence. These CNFs span a structurally diverse and largely non\u2010redundant set of domains, most of which lack clear sequence or structural similarity to known folds. Many CNFs appear as insertions into known transmembrane or enzymatic domains, while others occur in modular architectures, co\u2010occurring with interaction or catalytic folds such as \u03b2\u2010barrels, zinc fingers, or Rossmann\u2010like domains. Although some CNFs resemble known folds that have undergone topological rearrangements or circular permutations, others result from errors in domain boundary prediction, often due to truncated sequences or tightly packed domain duplications. Our analyses led to the creation of 190 new Pfam families, many classified as domains of unknown function (DUFs), and revealed intriguing cases of zinc\u2010binding and disulfide\u2010rich architectures that contribute to fold space expansion. A small subset of CNFs helped define new superfamilies by linking previously unclassified but structurally related domains. Taken together, this work underscores the importance of integrating structural, evolutionary, and contextual information to resolve challenging fold assignments and provides a roadmap for extending protein classification frameworks into previously uncharted structural territory.<\/jats:p>","DOI":"10.1002\/pro.70392","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T13:31:52Z","timestamp":1764077512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Terra incognita of\n                    <scp>AI<\/scp>\n                    \u2010based domain classifications"],"prefix":"10.1002","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3505-9665","authenticated-orcid":false,"given":"Jimin","family":"Pei","sequence":"first","affiliation":[{"name":"Eugene McDermott Center for Human Growth and Development University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Department of Biophysics University of Texas Southwestern Medical Center  Dallas Texas USA"},{"name":"Harold C. 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