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A layered computational workflow was implemented to predict pathogenicity, evaluate structural stability, and assess residue conservation. Subsequent modeling of protein dynamics included structural perturbation analyses, molecular docking, and long-timescale molecular dynamics simulations. Findings revealed that the D253N variant in MMP8 induces substantial deviations from native architecture, characterized by reduced molecular dimensions, lower solvent accessibility, and a broader conformational ensemble. Y261S, by contrast, preserved global folding features with restrained atomic fluctuations. In GZMK, the L122P mutation significantly increased local flexibility and altered compactness, while A42P had minor impact. The W216C substitution in OASL disrupted packing density and expanded surface exposure, indicating a relaxation of the native fold. Principal component analysis confirmed that D253N, L122P, and W216C drive enhanced structural variance relative to native forms. Despite retained ligand-binding capacity, structural rearrangements affected interaction patterns in docking complexes. These findings underscore the potential role of these variants in modifying protein behavior during immune responses. The results serve as a foundation for downstream validation studies on their involvement in infection susceptibility and immune dysregulation.<\/jats:p>","DOI":"10.1038\/s41598-026-40467-w","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T17:04:41Z","timestamp":1773162281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In silico structural and functional characterization of high-risk missense variants in MMP8, GZMK, and OASL genes associated with epidemic viral infections"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2559-7223","authenticated-orcid":false,"given":"Mohamed","family":"Et-tanjaouy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5487-5684","authenticated-orcid":false,"given":"Asmae","family":"Saih","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2349-3296","authenticated-orcid":false,"given":"Omar","family":"Machich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9476-0489","authenticated-orcid":false,"given":"Abdelkrim","family":"Guendouzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8750-9106","authenticated-orcid":false,"given":"Younes","family":"Zaid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1228-4931","authenticated-orcid":false,"given":"Hanaa","family":"Abdelmoumen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"40467_CR1","unstructured":"World Health Organization. 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