{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:11:32Z","timestamp":1790878292505,"version":"4.1.0"},"reference-count":414,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T00:00:00Z","timestamp":1516752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyloid-\u03b2 and \u03b1-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer\u2019s and Parkinson\u2019s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-\u03b2 and \u03b1-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer\u2019s and Parkinson\u2019s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-\u03b2 and \u03b1-synuclein in relation to the pathologies of Alzheimer\u2019s and Parkinson\u2019s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer\u2019s and Parkinson\u2019s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-\u03b2 and \u03b1-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-\u03b2 and \u03b1-synuclein, such as \u03b2-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer\u2019s and Parkinson\u2019s diseases. This information represents an important foundation for the successful and efficient drug design studies.<\/jats:p>","DOI":"10.3390\/ijms19020336","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T09:47:36Z","timestamp":1516787256000},"page":"336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Insights into the Molecular Mechanisms of Alzheimer\u2019s and Parkinson\u2019s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology"],"prefix":"10.3390","volume":"19","author":[{"given":"Orkid","family":"Coskuner-Weber","sequence":"first","affiliation":[{"name":"T\u00fcrkisch-Deutsche Universit\u00e4t, Theoretical and Computational Biophysics Group, Molecular Biotechnology, Sahinkaya Caddesi, No. 86, Beykoz, Istanbul 34820, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-5857","authenticated-orcid":false,"given":"Vladimir","family":"Uversky","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and USF Health Byrd Alzheimer\u2019s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1749-6632.2003.tb07465.x","article-title":"The cast of molecular characters in Parkinson\u2019s disease: Felons, conspirators, and suspects","volume":"991","author":"Lim","year":"2003","journal-title":"Ann. 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