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The in\u2009vitro selectivity of proteins for transition metal ions is largely governed by the Irving\u2013Williams series, which states protein\u2010metal complex stability follows the order Co(II) &lt; Ni(II) &lt; Cu(II) &gt; Zn(II). A de\u2009novo protein has been designed that folds in the presence of certain transition metal ions into a monomeric \u03b1\u2010helical bundle, with the least stable protein\u2010metal complex being formed with Cu(II). Moreover, when increasing the metal concentration of Cu(II) or Zn(II), more metal ions are incorporated into the protein accompanied by a concurrent decrease in the amount of secondary structure. One reason may be that there is a balance between stability conferred by the coordination of the metal ion(s) and stability conferred by hydrophobic packing of the \u03b1\u2010helical bundle. Metals may therefore adopt distorted coordination geometries, or binding of multiple ions may cause distortion of the protein backbone, leading to compromised folding of the protein scaffold, or variable thermal stabilities of the metalloprotein complexes. This protein scaffold therefore contributes to the deciphering of design rules for metal selectivity in proteins.<\/jats:p>","DOI":"10.1002\/cbic.202500322","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T17:11:27Z","timestamp":1748452287000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A De Novo Designed Metalloprotein Displays Variable Thermal Stability and Binding Stoichiometry with Transition Metal Ions"],"prefix":"10.1002","volume":"26","author":[{"given":"Britt","family":"Rooijakkers","sequence":"first","affiliation":[{"name":"Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaya","family":"Verhagen","sequence":"additional","affiliation":[{"name":"Leiden Institute of Chemistry Leiden University  Einsteinweg 55 2333 CC Leiden 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