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Here, we present a systematic Quantum-Mechanics\/Molecular-Mechanics (QM\/MM) study of the full Ln series (La\u2013Lu) using the \u03c9B97X-D4rev exchange-correlation functional. Structurally, we identify a substrate-dependent coordination switch: in the Michaelis\u2013Menten complex, the biologically relevant light Ln (La\u2013Gd) maintains a 10-coordinate geometry, whereas a discrete transition to a 9-coordinate state occurs from Tb onward, driven by the shift of the essential Asp301 from bidentate to monodentate coordination mode. Notably, this shift is absent in the substrate-free enzyme, indicating that substrate binding enforces the steric crowding that disfavors heavier metals. Energetic analysis reveals that within the biologically relevant window (La\u2013Gd), substrate affinity is mostly uniform, while enzyme binding affinity exhibits a clear and steady preference for the lighter metals. These results demonstrate that biological lanthanide selection in MDH arises from a combination of higher binding affinity for early lanthanides and their ability to preserve a catalytically competent 10-coordinate geometry, rather than from differential substrate binding. Taken together, our findings provide a structural and energetic framework for understanding the coordination properties of the lanthanide series in the active site of the MDH and may guide further QM\/MM studies on the reaction mechanism of this enzyme as well as the engineering of lanthanide-dependent biocatalysts.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c03103","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:13:27Z","timestamp":1788304407000},"page":"9070-9083","source":"Crossref","is-referenced-by-count":1,"title":["QM\/MM Reveals Coordination\nShift behind Early Lanthanide\nPreference in Methanol Dehydrogenase XoxF"],"prefix":"10.1021","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4638-1091","authenticated-orcid":true,"given":"Emiliano Isai\u0301as","family":"Alani\u0301s-Manzano","sequence":"first","affiliation":[{"name":"Universidad Nacional Auto\u0301noma de Me\u0301xico , , ,","place":["Cuernavaca Morelos, Me\u0301xico, 62210"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4941-6619","authenticated-orcid":true,"given":"Jose\u0301 Luis","family":"Vela\u0301zquez-Libera","sequence":"additional","affiliation":[{"name":"Universidad de Talca , , ,","place":["Talca, Chile, 3460000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ce\u0301sar","family":"Millan Pacheco","sequence":"additional","affiliation":[{"name":"Universidad Auto\u0301noma del Estado de Morelos , , , ,","place":["Cuernavaca, Morelos, Me\u0301xico, 62209"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8428-5714","authenticated-orcid":true,"given":"Alejandro","family":"Rami\u0301rez-Soli\u0301s","sequence":"additional","affiliation":[{"name":"Universidad Auto\u0301noma del Estado de Morelos , , , ,","place":["Cuernavaca, Morelos, Me\u0301xico, 62209"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humberto","family":"Saint-Martin","sequence":"additional","affiliation":[{"name":"Universidad Nacional Auto\u0301noma de Me\u0301xico , , ,","place":["Cuernavaca Morelos, Me\u0301xico, 62210"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026091008081043500_cit1","first-page":"1","article-title":"A Perspective on the Role of Lanthanides in Biology: Discovery, Open\nQuestions and Possible Applications","volume-title":"Advances\nin Microbial Physiology","author":"Daumann","year":"2022"},{"key":"2026091008081043500_cit2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/B978-0-443-13307-7.00001-3","article-title":"Lanthanide Utilization\nby Organisms: An Overview","volume-title":"Lanthanides\nin Enzymology and Microbiology","author":"Tani","year":"2025"},{"key":"2026091008081043500_cit3","doi-asserted-by":"publisher","DOI":"10.1093\/ismejo\/wrae241","article-title":"Emerging role of rare\nearth elements in biomolecular functions","volume":"19","author":"Yang","year":"2024","journal-title":"ISME\nJ."},{"key":"2026091008081043500_cit4","doi-asserted-by":"publisher","DOI":"10.1111\/1751-7915.14503","article-title":"Rare earth elements in biology: From\nbiochemical curiosity to solutions for extractive industries","volume":"17","author":"Rocha","year":"2024","journal-title":"Microb. 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