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Pathogenic variants are associated with a broad clinical spectrum, from severe Hurler syndrome to attenuated Scheie phenotype. The missense mutations L490P and P533R cause attenuated\u2010intermediate MPS I, retaining residual enzyme activity. To investigate the structural mechanisms underlying these phenotypes, we performed all\u2010atom molecular dynamics simulations \u201318 trajectories of 1.6\u2009\u03bcs each\u2013 comparing wild type IDUA with L490P and P533R mutants at pH\u20097.5 and 4.5, mimicking the endoplasmic reticulum (ER) and lysosomal microenvironments, respectively. Backbone root\u2010mean\u2010square deviation and fluctuation analyses indicated that the overall protein fold was maintained across conditions; however, we identified a pH\u2010dependent restricted conformational flexibility of the N372\u2010linked glycan in both mutants. Cluster analysis performed on the obtained trajectories showed that both mutations affect the conformation of this glycan. Hydrogen bond analysis further revealed that P533R induces aberrant, persistent glycan\u2013protein interactions, providing a possible structural explanation for reduced IDUA activity and, therefore, GAG processing. Our findings, supported by in\u00a0vitro data, propose glycan conformational restriction as a possible new molecular mechanism that underpins enzymatic dysfunction in attenuated MPS I, opening new avenues for structure\u2010informed therapeutic strategies.<\/jats:p>","DOI":"10.1111\/jcmm.71396","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T02:40:35Z","timestamp":1791772835000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Dynamics Reveals a Glycan Conformation Underlying\n                    <scp>IDUA<\/scp>\n                    Dysfunction in Attenuated\n                    <scp>MPS<\/scp>\n                    I"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6072-3388","authenticated-orcid":false,"given":"Maria Giovanna Eva","family":"Papadopoulos","sequence":"first","affiliation":[{"name":"CNR\u2013Institute of 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9475-9602","authenticated-orcid":false,"given":"Domenico","family":"Alberga","sequence":"additional","affiliation":[{"name":"CNR\u2013Institute of Crystallography  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-2841","authenticated-orcid":false,"given":"Giuseppe Felice","family":"Mangiatordi","sequence":"additional","affiliation":[{"name":"CNR\u2013Institute of Crystallography  Bari 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