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To address this issue, we design two compounds by covalently grafting isomeric ortho\u2010vanillin or vanillin onto a MnMo\n                    <jats:sub>6<\/jats:sub>\n                    cluster. The resulting o\u2010Va\u2010MnMo\n                    <jats:sub>6<\/jats:sub>\n                    \u00a0exhibits markedly superior disassembly activity, reducing neurotoxic PrP106\u2010126 aggregates by 85% versus 49% for Va\u2010MnMo\n                    <jats:sub>6<\/jats:sub>\n                    . The enhanced efficacy arises from the ortho\u2010methoxy group of o\u2010Va\u2010MnMo\n                    <jats:sub>6<\/jats:sub>\n                    , which engages hydrophobic Ala113 via van der Waals interactions, whilst its hydroxyl group forms a hydrogen bond with the M112\u2010A113 backbone. Concurrently, the polyoxometalate moiety electrostatically interacts with Lys110. The multipoint binding enables the molecule to straddle the contiguous K\n                    <jats:sup>110<\/jats:sup>\n                    HMA\n                    <jats:sup>113<\/jats:sup>\n                    domain, effectively disrupting the aggregation core. In contrast, Va\u2010MnMo\n                    <jats:sub>6<\/jats:sub>\n                    interacts primarily with His111 via hydrogen bonding, lacking critical hydrophobic contact. Molecular dynamics simulations confirm that both compounds initially anchor electrostatically to Lys110, after which their differing ligands guide them to distinct sites, resulting in the divergent potencies.\n                  <\/jats:p>","DOI":"10.1002\/smll.75485","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:52:02Z","timestamp":1787817122000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Divergent Disassembly of PrP106\u2010126 Aggregates Driven by Isomeric Polyoxometalate Hybrids"],"prefix":"10.1002","author":[{"given":"Siyu","family":"Liang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemical Resource Engineering Beijing University of Chemical Technology  Beijing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key 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