{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T22:31:10Z","timestamp":1772836270269,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21973035"],"award-info":[{"award-number":["21973035"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["RP\/FCA-01\/2022"],"award-info":[{"award-number":["RP\/FCA-01\/2022"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Macao Polytechnic University","award":["21973035"],"award-info":[{"award-number":["21973035"]}]},{"name":"Macao Polytechnic University","award":["RP\/FCA-01\/2022"],"award-info":[{"award-number":["RP\/FCA-01\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The aggregation of alpha-synuclein (\u03b1-Syn) is closely related to the occurrence of some neurodegenerative diseases such as Parkinson\u2019s disease. The misfolding of \u03b1-Syn monomer plays a key role in the formation of aggregates and extension of fibril. However, the misfolding mechanism of \u03b1-Syn remains elusive. Here, three different \u03b1-Syn fibrils (isolated from a diseased human brain, generated by in vitro cofactor-tau induction, and obtained by in vitro cofactor-free induction) were selected for the study. The misfolding mechanisms of \u03b1-Syn were uncovered by studying the dissociation of the boundary chains based on the conventional molecular dynamics (MD) and Steered MD simulations. The results showed that the dissociation paths of the boundary chains in the three systems were different. According to the reverse process of dissociation, we concluded that in the human brain system, the binding of the monomer and template starts from the C-terminal and gradually misfolds toward the N-terminal. In the cofactor-tau system, the monomer binding starts from residues 58\u201366 (contain \u03b23), followed by the C-terminal coil (residues 67\u201379). Then, the N-terminal coil (residues 36\u201341) and residues 50\u201357 (contain \u03b22) bind to the template, followed by residues 42\u201349 (contain \u03b21). In the cofactor-free system, two misfolding paths were found. One is that the monomer binds to the N\/C-terminal (\u03b21\/\u03b26) and then binds to the remaining residues. The other one is that the monomer binds sequentially from the C- to N-terminal, similar to the human brain system. Furthermore, in the human brain and cofactor-tau systems, electrostatic interactions (especially from residues 58\u201366) are the main driving force during the misfolding process, whereas in the cofactor-free system, the contributions of electrostatic and van der Waals interactions are comparable. These results may provide a deeper understanding for the misfolding and aggregation mechanism of \u03b1-Syn.<\/jats:p>","DOI":"10.3390\/biom13040682","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T03:14:09Z","timestamp":1681701249000},"page":"682","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The \u03b1-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of \u03b1-Synuclein Fibrils with Different Polymorphs"],"prefix":"10.3390","volume":"13","author":[{"given":"Nannan","family":"Zhao","sequence":"first","affiliation":[{"name":"School of Pharmacy, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences, Macao Polytechnic University, Macao SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fansen","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojun","family":"Yao","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-3667","authenticated-orcid":false,"given":"Huanxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Lanzhou University, Lanzhou 730000, China"},{"name":"Faculty of Applied Sciences, Macao Polytechnic University, Macao SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-Propagation of Pathogenic Protein Aggregates in Neurodegenerative Diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Surguchov, A., and Surguchev, A. 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