{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T15:41:27Z","timestamp":1793202087335,"version":"4.5.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p><jats:italic>\u03b1<\/jats:italic>-Synuclein is an intrinsically disordered protein occurring in different conformations and prone to aggregate in <jats:italic>\u03b2<\/jats:italic>-sheet structures, which are the hallmark of the Parkinson disease. Missense mutations are associated with familial forms of this neuropathy. How these single amino-acid substitutions modify the conformations of wild-type <jats:italic>\u03b1<\/jats:italic>-synuclein is unclear. Here, using coarse-grained molecular dynamics simulations, we sampled the conformational space of the wild type and mutants (A30P, A53P, and E46K) of <jats:italic>\u03b1<\/jats:italic>-synuclein monomers for an effective time scale of 29.7\u00a0ms. To characterize the structures, we developed an algorithm, CUTABI (CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification), to identify residues in the <jats:italic>\u03b1<\/jats:italic>-helix and <jats:italic>\u03b2<\/jats:italic>-sheet from <jats:italic>C<jats:sup>\u03b1<\/jats:sup><\/jats:italic>-coordinates. CUTABI was built from the results of the analysis of 14,652 selected protein structures using the Dictionary of Secondary Structure of Proteins (DSSP) algorithm. DSSP results are reproduced with 93% of success for 10 times lower computational cost. A two-dimensional probability density map of <jats:italic>\u03b1<\/jats:italic>-synuclein as a function of the number of residues in the <jats:italic>\u03b1<\/jats:italic>-helix and <jats:italic>\u03b2<\/jats:italic>-sheet is computed for wild-type and mutated proteins from molecular dynamics trajectories. The density of conformational states reveals a two-phase characteristic with a homogeneous phase (state B, <jats:italic>\u03b2<\/jats:italic>-sheets) and a heterogeneous phase (state HB, mixture of <jats:italic>\u03b1<\/jats:italic>-helices and <jats:italic>\u03b2<\/jats:italic>-sheets). The B state represents 40% of the conformations for the wild-type, A30P, and E46K and only 25% for A53T. The density of conformational states of the B state for A53T and A30P mutants differs from the wild-type one. In addition, the mutant A53T has a larger propensity to form helices than the others. These findings indicate that the equilibrium between the different conformations of the <jats:italic>\u03b1<\/jats:italic>-synuclein monomer is modified by the missense mutations in a subtle way. The <jats:italic>\u03b1<\/jats:italic>-helix and <jats:italic>\u03b2<\/jats:italic>-sheet contents are promising order parameters for intrinsically disordered proteins, whereas other structural properties such as average gyration radius, <jats:italic>R<\/jats:italic><jats:sub><jats:italic>g<\/jats:italic><\/jats:sub>, or probability distribution of <jats:italic>R<\/jats:italic><jats:sub><jats:italic>g<\/jats:italic><\/jats:sub> cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of <jats:italic>R<\/jats:italic><jats:sub><jats:italic>g<\/jats:italic><\/jats:sub> are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the <jats:italic>\u03b1<\/jats:italic>-synuclein monomer.<\/jats:p>","DOI":"10.3389\/fmolb.2021.786123","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T13:59:51Z","timestamp":1638367191000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Missense Mutations Modify the Conformational Ensemble of the \u03b1-Synuclein Monomer Which Exhibits a Two-Phase Characteristic"],"prefix":"10.3389","volume":"8","author":[{"given":"Adrien","family":"Guzzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Delarue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Nicola\u00ef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gia G.","family":"Maisuradze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Senet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"18314","DOI":"10.1021\/ja904716h","article-title":"Determination of the Free Energy Landscape of \u03b1-Synuclein Using Spin Label Nuclear Magnetic Resonance Measurements","volume":"131","author":"Allison","year":"2009","journal-title":"J. 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