{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:46:58Z","timestamp":1753890418290,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>The Prion protein is the molecular hallmark of the incurable prion diseases affecting mammals, including humans. The protein-only hypothesis states that the misfolding, accumulation, and deposition of the Prion protein play a critical role in toxicity. The cellular Prion protein (PrP<jats:sup>C<\/jats:sup>) anchors to the extracellular leaflet of the plasma membrane and prefers cholesterol- and sphingomyelin-rich membrane domains. Conformational Prion protein conversion into the pathological isoform happens on the cell surface. <jats:italic>In vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> experiments indicate that Prion protein misfolding, aggregation, and toxicity are sensitive to the lipid composition of plasma membranes and vesicles. A picture of the underlying biophysical driving forces that explain the effect of Prion protein - lipid interactions in physiological conditions is needed to develop a structural model of Prion protein conformational conversion. To this end, we use molecular dynamics simulations that mimic the interactions between the globular domain of PrP<jats:sup>C<\/jats:sup> anchored to model membrane patches. In addition, we also simulate the Doppel protein anchored to such membrane patches. The Doppel protein is the closest in the phylogenetic tree to PrP<jats:sup>C<\/jats:sup>, localizes in an extracellular milieu similar to that of PrP<jats:sup>C<\/jats:sup>, and exhibits a similar topology to PrP<jats:sup>C<\/jats:sup> even if the amino acid sequence is only 25% identical. Our simulations show that specific protein-lipid interactions and conformational constraints imposed by GPI anchoring together favor specific binding sites in globular PrP<jats:sup>C<\/jats:sup> but not in Doppel. Interestingly, the binding sites we found in PrP<jats:sup>C<\/jats:sup> correspond to prion protein loops, which are critical in aggregation and prion disease transmission barrier (\u03b22-\u03b12 loop) and in initial spontaneous misfolding (\u03b12-\u03b13 loop). We also found that the membrane re-arranges locally to accommodate protein residues inserted in the membrane surface as a response to protein binding.<\/jats:p>","DOI":"10.3389\/fbinf.2023.1321287","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T04:47:50Z","timestamp":1704430070000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein-lipid interactions and protein anchoring modulate the modes of association of the globular domain of the Prion protein and Doppel protein to model membrane patches"],"prefix":"10.3389","volume":"3","author":[{"given":"Patricia","family":"Soto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davis T.","family":"Thalhuber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Luceri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"Janos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mason R.","family":"Borgman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noah M.","family":"Greenwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Acosta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hunter","family":"Stoffel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"43295","DOI":"10.1038\/srep43295","article-title":"Post-translational modifications in PrP expand the conformational diversity of prions in vivo","volume":"7","author":"Aguilar-Calvo","year":"2017","journal-title":"Sci. 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