{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:36:22Z","timestamp":1762673782957},"reference-count":66,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2010,11,8]],"date-time":"2010-11-08T00:00:00Z","timestamp":1289174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prion propagation in transmissible spongiform encephalopathies involves the conversion of the cellular prion protein, PrP<jats:sup>C<\/jats:sup>, into the pathogenic conformer PrP<jats:sup>Sc<\/jats:sup>. Human familial forms of the disease are linked to specific mutations in the PrP gene, <jats:italic>PRNP<\/jats:italic>, and include Gerstmann\u2010Str\u00e4ussler\u2010Scheinker syndrome (GSS), familial Creutzfeldt\u2010Jakob disease (fCJD), and fatal familial insomnia. To gain insights into the molecular basis of these disorders, we performed 200 ns of classical molecular dynamic simulations in aqueous solution on wild type (WT) human PrP (HuPrP), and on three HuPrP variants located in the globular HuPrP domain: two pathological mutations, HuPrP(Q212P) and HuPrP(E200K), linked to GSS and to fCJD respectively, and one protective polymorphism, HuPrP(E219K) (total time\u2010scale simulated 800 ns). A comparison between the predicted structural determinants of WT HuPrP and HuPrP(E200K) with their NMR structures established the accuracy of the methods used. Strikingly, the analyzed disease\u2010linked variants produced their major effect on the \u03b1<jats:sub>2<\/jats:sub>\u2010\u03b1<jats:sub>3<\/jats:sub> region and the \u03b2<jats:sub>2<\/jats:sub>\u2010\u03b1<jats:sub>2<\/jats:sub> loop, regardless of the mutation position. The conformational change of the latter might affect the interactions with cellular partners in the fibrillation process. The protocol proposed here represents a powerful approach for reproducing the structural effects of genetic mutations located in the globular domain of HuPrP, such as the GSS\u2010related HuPrP(Q212P) and the protective polymorphism HuPrP(E219K). Proteins 2010. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22834","type":"journal-article","created":{"date-parts":[[2010,7,23]],"date-time":"2010-07-23T15:09:34Z","timestamp":1279897774000},"page":"3270-3280","source":"Crossref","is-referenced-by-count":43,"title":["Structural facets of disease\u2010linked human prion protein mutants: A molecular dynamic 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