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However, the molecular role of this post\u2010translational modification (PTM) in driving tau aggregation remains unclear. In\u2010register fibril assembly places phosphoryl groups on adjacent monomers at \u223c4.8\u00a0\u00c5 spacing, requiring an energetically favorable arrangement. Conventional intuition holds that closely packed phosphoryl groups should be electrostatically unfavorable. We test the opposing hypothesis: that phosphoryl groups within the fibril core associate into an extended \u201cwire\u201d that stabilizes the amyloid fibril. We examined two phosphorylation sites linked to neurodegeneration, serine 305 (S305\n                    <jats:sup>p<\/jats:sup>\n                    ) and tyrosine 310 (Y310\n                    <jats:sup>p<\/jats:sup>\n                    ), using seeding\u2010competent fibrils of the tau peptide jR2R3\u2010P301L. Multiple\u2010quantum spin counting (MQ\u2010SC) by\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    P solid\u2010state NMR with dynamic nuclear polarization (DNP) revealed at least six phosphorus spins linearly arranged within a protofibril, consistent with a MQ coherence order of four. Molecular dynamics simulations identified water\u2010mediated phosphoryl wire geometries, and 2D\n                    <jats:sup>1<\/jats:sup>\n                    H\u2013\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    P heteronuclear correlation NMR confirmed water\u2010bridged phosphoryl\u2010phosphoryl contacts. Denaturation experiments showed that S305 phosphorylation increased fibril stability relative to the unmodified peptide. These findings show that phosphorylation within the tau fibril core promotes fibril registry and stability through water\u2010mediated, hydrogen\u2010bonded phosphoryl wires, which may be a structural signature for next\u2010generation pathological tau binders.\n                  <\/jats:p>","DOI":"10.1002\/anie.202521499","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T11:53:20Z","timestamp":1779537200000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Water\u2010Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1321-9784","authenticated-orcid":false,"given":"Lokeswara Rao","family":"Potnuru","sequence":"first","affiliation":[{"name":"Department of Chemistry Northwestern University  Evanston Illinois 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