{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T22:47:12Z","timestamp":1790462832450,"version":"4.1.0"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T00:00:00Z","timestamp":1596672000000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM44557"],"award-info":[{"award-number":["R01 GM44557"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DR Bullard-Welch of Sciences, Rice University","award":["Grant C-0016"],"award-info":[{"award-number":["Grant C-0016"]}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["Grant OCI-0959097"],"award-info":[{"award-number":["Grant OCI-0959097"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Theoretical Biological Physics, Rice University","award":["PHY-1427654."],"award-info":[{"award-number":["PHY-1427654."]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,2,25]]},"abstract":"<jats:p>\n                    Filaments made up of different isoforms of tau protein are associated with a variety of neurodegenerative diseases. Filaments made up of the 4R-tau isoform, which has four repeat regions (R1 to R4), are found in patients suffering from Alzheimer\u2019s disease, while filaments made of the 3R-tau isoform, which contains only three repeat units (R1, R3, and R4), are found in patients with Pick\u2019s disease (frontotemporal dementia). In this work, a predictive coarse-grained protein force field, the associative memory water-mediated structure and energy model (AWSEM), is used to study the energy landscapes of nucleation of the two different fibrils derived from patients with Pick\u2019s and Alzheimer\u2019s diseases. The landscapes for nucleating both fibril types contain amorphous oligomers leading to branched structures as well as prefibrillar oligomers. These two classes of oligomers differ in their structural details: The prefibrillar oligomers have more parallel in-register\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                        <mml:mi>\u03b2<\/mml:mi>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    -strands, which ultimately lead to amyloid fibrils, while the amorphous oligomers are characterized by a near random\n                    <jats:inline-formula>\n                      <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" overflow=\"scroll\">\n                        <mml:mi>\u03b2<\/mml:mi>\n                      <\/mml:math>\n                    <\/jats:inline-formula>\n                    -strand stacking, leading to a distinct amorphous phase. The landscape topography suggests that there must be significant structural reordering, or \u201cbacktracking,\u201d to transit from the amorphous aggregation channel to the fibrillization channel. Statistical mechanical perturbation theory allows us to evaluate the effects of changing concentration on the aggregation free-energy landscapes and to predict the effects of phosphorylation, which is known to facilitate the aggregation of tau repeats.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1921702117","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T20:06:24Z","timestamp":1581019584000},"page":"4125-4130","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":41,"title":["Exploring the interplay between fibrillization and amorphous aggregation channels on the energy landscapes of tau repeat isoforms"],"prefix":"10.1073","volume":"117","author":[{"given":"Xun","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Theoretical Biological Physics, Rice University, Houston, TX 77005;"},{"name":"Department of Chemistry, Rice University, Houston, TX 77005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingchen","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Theoretical Biological Physics, Rice University, Houston, TX 77005;"},{"name":"Department of Bioengineering, Rice University, Houston, TX 77005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P.","family":"Schafer","sequence":"additional","affiliation":[{"name":"Center for Theoretical Biological Physics, Rice University, Houston, TX 77005;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7975-9287","authenticated-orcid":false,"given":"Peter G.","family":"Wolynes","sequence":"additional","affiliation":[{"name":"Center for Theoretical Biological Physics, Rice University, Houston, TX 77005;"},{"name":"Department of Chemistry, Rice University, Houston, TX 77005;"},{"name":"Department of Biosciences, Rice University, Houston, TX 77005"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,2,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nrn.2015.1","article-title":"Tau in physiology and pathology","volume":"17","author":"Wang Y.","year":"2016","unstructured":"Y. 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Wolynes, Comparing the aggregation free energy landscapes of amyloid beta (1\u201342) and amyloid beta (1\u201340). J. Am. Chem. Soc. 139, 16666\u201316676 (2017).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"15197","DOI":"10.1021\/jacs.6b08665","article-title":"The aggregation free energy landscapes of polyglutamine repeats","volume":"138","author":"Chen M.","year":"2016","unstructured":"M. Chen, M. Y. Tsai, W. Zheng, P. G. Wolynes, The aggregation free energy landscapes of polyglutamine repeats. J. Am. Chem. Soc. 138, 15197\u201315203 (2016).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1073\/pnas.1702237114","article-title":"Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington\u2019s disease","volume":"114","author":"Chen M.","year":"2017","unstructured":"M. Chen, P. G. 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