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Here, we challenge this view by examining the folding behavior of full-length Staphylococcal protein A (SpA), a 516-residue multidomain protein containing five immunoglobulin (Ig)-binding domains. Although each of the five Ig-binding domains of SpA folds stably in isolation (as it is already known experimentally and also confidently predicted by AI models), here, we show that the full-length construct and the individual Ig-binding domains in the full-length construct fail to adopt a stable three-dimensional structure in solution (despite being predicted to be folded by AI models). Instead, full-length SpA populates a compact yet predominantly disordered ensemble with residual secondary structure, where the folded state of each Ig-binding domain is thermodynamically unfavorable. These findings not only challenge long-held assumptions about the modular architecture and stability of SpA but also underscore the limitations of AI-based predictors when decoupled from the thermodynamic context. This work has implications for validating structure predictions, understanding multidomain architecture, and designing modular proteins for biotechnology and medicine.<\/jats:p>","DOI":"10.64898\/2025.12.08.692973","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T19:30:35Z","timestamp":1765308635000},"source":"Crossref","is-referenced-by-count":0,"title":["Full-Length Context Disrupts Folding of IgG-Binding Domains of Protein A"],"prefix":"10.64898","author":[{"given":"Kosar","family":"Rahimi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Halbing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh Ngoc","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Willson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcl H.","family":"Zerze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121104500778000_2025.12.08.692973v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.06.022"},{"key":"2025121104500778000_2025.12.08.692973v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2014.06.011"},{"key":"2025121104500778000_2025.12.08.692973v1.3","doi-asserted-by":"crossref","first-page":"167087","DOI":"10.1016\/j.jmb.2021.167087","article-title":"Probing the effects of local frustration in the folding of a multidomain protein","volume":"433","year":"2021","journal-title":"Journal of Molecular Biology"},{"key":"2025121104500778000_2025.12.08.692973v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2014.08.014"},{"key":"2025121104500778000_2025.12.08.692973v1.5","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaf340"},{"key":"2025121104500778000_2025.12.08.692973v1.6","unstructured":"Lin, R. 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