{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:17:04Z","timestamp":1790623024252,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T00:00:00Z","timestamp":1580342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009045","name":"Uniwersytet Jagiello\u0144ski Collegium Medicum","doi-asserted-by":"publisher","award":["N41\/DBS\/000211"],"award-info":[{"award-number":["N41\/DBS\/000211"]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The object of our analysis is the structure of alpha-synuclein (ASyn), which, under in vivo conditions, associates with presynaptic vesicles. Misfolding of ASyn is known to be implicated in Parkinson\u2019s disease. The availability of structural information for both the micelle-bound and amyloid form of ASyn enables us to speculate on the specific mechanism of amyloid transformation. This analysis is all the more interesting given the fact that\u2014Unlike in A\u03b2(1\u201342) amyloids\u2014only the central fragment (30\u2013100) of ASyn has a fibrillar structure, whereas, its N- and C-terminal fragments (1\u201330 and 100\u2013140, respectively) are described as random coils. Our work addresses the following question: Can the ASyn chain\u2014as well as the aforementioned individual fragments\u2014adopt globular conformations? In order to provide an answer, we subjected the corresponding sequences to simulations carried out using Robetta and I-Tasser, both of which are regarded as accurate protein structure predictors. In addition, we also applied the fuzzy oil drop (FOD) model, which, in addition to optimizing the protein\u2019s internal free energy, acknowledges the presence of an external force field contributed by the aqueous solvent. This field directs hydrophobic residues to congregate near the center of the protein body while exposing hydrophilic residues on its surface. Comparative analysis of the obtained models suggests that fragments which do not participate in forming the amyloid fibril (i.e., 1\u201330 and 100\u2013140) can indeed attain globular conformations. We also explain the influence of mutations observed in vivo upon the susceptibility of ASyn to undergo amyloid transformation. In particular, the 30\u2013100 fragment (which adopts a fibrillar structure in PDB) is not predicted to produce a centralized hydrophobic core by any of the applied toolkits (Robetta, I-Tasser, and FOD). This means that in order to minimize the entropically disadvantageous contact between hydrophobic residues and the polar solvent, ASyn adopts the form of a ribbonlike micelle (rather than a spherical one). In other words, the ribbonlike micelle represents a synergy between the conformational preferences of the protein chain and the influence of its environment.<\/jats:p>","DOI":"10.3390\/molecules25030600","type":"journal-article","created":{"date-parts":[[2020,1,31]],"date-time":"2020-01-31T05:55:46Z","timestamp":1580450146000},"page":"600","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Alternative Structures of \u03b1-Synuclein"],"prefix":"10.3390","volume":"25","author":[{"given":"Dawid","family":"Du\u0142ak","sequence":"first","affiliation":[{"name":"Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, \u0141ojasiewicza 11, 30-348 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Gadza\u0142a","sequence":"additional","affiliation":[{"name":"ACK\u2013Cyfronet AGH, Nawojki 11, 30-950 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-9877","authenticated-orcid":false,"given":"Mateusz","family":"Banach","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Telemedicine, Jagiellonian University\u2014Medical College, \u0141azarza 16, 31-530 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Konieczny","sequence":"additional","affiliation":[{"name":"Chair of Medical Biochemistry, Jagiellonian University\u2013Medical College, Kopernika 7, 31-034 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3652-9099","authenticated-orcid":false,"given":"Irena","family":"Roterman","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Telemedicine, Jagiellonian University\u2014Medical College, \u0141azarza 16, 31-530 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.cell.2005.10.017","article-title":"Snaring the Function of \u03b1-Synuclein","volume":"123","author":"Bonini","year":"2005","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/0896-6273(95)90302-X","article-title":"The precursor protein of non-A\u03b2 component of Alzheimer\u2019s disease amyloid is a presynaptic protein of the central nervous system","volume":"14","author":"Iwai","year":"1995","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35863","DOI":"10.1074\/jbc.M111.253450","article-title":"Effect of Ser-129 Phosphorylation on Interaction of \u03b1-Synuclein with Synaptic and Cellular Membranes*","volume":"286","author":"Visanji","year":"2011","journal-title":"J. Boil. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1385\/NMM:2:2:115","article-title":"Alpha-Synuclein and Presynaptic Function: Implications for Parkinson\u2019s Disease","volume":"2","author":"Lykkebo","year":"2002","journal-title":"NeuroMol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/bs.ircmb.2016.08.010","article-title":"Structural Characteristics of \u03b1-Synuclein Oligomers","volume":"329","author":"Cremades","year":"2017","journal-title":"Int. Rev. Cell. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.1038\/ncomms4827","article-title":"Direct observation of the three regions in \u03b1-synuclein that determine its membrane-bound behaviour","volume":"5","author":"Fusco","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1126\/science.1195227","article-title":"Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro","volume":"329","author":"Sharma","year":"2010","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neuron.2009.12.023","article-title":"Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis","volume":"65","author":"Nemani","year":"2010","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nsmb.3194","article-title":"Solid-state NMR structure of a pathogenic fibril of full-length human \u03b1-synuclein","volume":"23","author":"Tuttle","year":"2016","journal-title":"Nat. Struct. Mol. Boil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.str.2014.10.022","article-title":"Modeling an In-Register, Parallel \u201cIowa\u201d A\u03b2 Fibril Structure Using Solid-State NMR Data from Labeled Samples with Rosetta","volume":"23","author":"Sgourakis","year":"2015","journal-title":"Structure"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nsmb.2991","article-title":"A\u03b2(1\u201342) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer\u2019s disease","volume":"22","author":"Xiao","year":"2015","journal-title":"Nat. Struct. Mol. Boil."},{"key":"ref_12","first-page":"331","article-title":"Atomic-Resolution Three-Dimensional Structure of Amyloid \u03b2 Fibrils Bearing the Osaka Mutation**","volume":"54","author":"Vagt","year":"2014","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9663","DOI":"10.1021\/jacs.6b05129","article-title":"Atomic Resolution Structure of Monomorphic A\u03b242 Amyloid Fibrils","volume":"138","author":"Colvin","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature23002","article-title":"Cryo-EM structures of tau filaments from Alzheimer\u2019s disease","volume":"547","author":"Fitzpatrick","year":"2017","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Banach, N., and Roterman, I. (2020). Amyloid as a ribbon-like micelle. From Globular Proteins to Amyloids, Elsevier.","DOI":"10.1016\/B978-0-08-102981-7.00016-6"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9595","DOI":"10.1074\/jbc.M411805200","article-title":"Structure and Dynamics of Micelle-bound Human -Synuclein","volume":"280","author":"Ulmer","year":"2004","journal-title":"J. Boil. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W526","DOI":"10.1093\/nar\/gkh468","article-title":"Protein structure prediction and analysis using the Robetta server","volume":"32","author":"Kim","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nprot.2010.5","article-title":"I-TASSER: A unified platform for automated protein structure and function prediction","volume":"5","author":"Roy","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/prot.24452","article-title":"Critical assessment of methods of protein structure prediction (CASP)-round x","volume":"82","author":"Moult","year":"2013","journal-title":"Proteins: Struct. Funct. Bioinform."},{"key":"ref_20","first-page":"15","article-title":"Gauss-function-Based model of hydrophobicity density in proteins","volume":"6","author":"Konieczny","year":"2006","journal-title":"Silico Boil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jmgm.2018.12.008","article-title":"The aqueous environment as an active participant in the protein folding process","volume":"87","author":"Kalinowska","year":"2019","journal-title":"J. Mol. Graph. Model."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.3390\/e17031477","article-title":"Application of Divergence Entropy to Characterize the Structure of the Hydrophobic Core in DNA Interacting Proteins","volume":"17","author":"Kalinowska","year":"2015","journal-title":"Entropy"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Du\u0142ak, D., Banach, M., Gadza\u0142a, M., Konieczny, L., and Roterman, I. (2018). Structural analysis of the A\u03b2(15-40) amyloid fibril based on hydrophobicity distribution. Acta Biochim. Pol.","DOI":"10.18388\/abp.2018_2647"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Du\u0142ak, D., Gadza\u0142a, M., Banach, M., Ptak, M., Wi\u015bniowski, Z., Konieczny, L., and Roterman, I. (2018). Filamentous Aggregates of Tau Proteins Fulfil Standard Amyloid Criteria Provided by the Fuzzy Oil Drop (FOD) Model. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201807.0275.v1"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Du\u0142ak, D., Gadza\u0142a, M., Stapor, K., Fabian, P., Konieczny, L., and Roterman, I. (2020). Holding with active paticipation of water. From Globular Proteins to Amyloids, Elsevier.","DOI":"10.1016\/B978-0-08-102981-7.00002-6"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Banach, M., Konieczny, L., and Roterman, I. (2018). Fuzzy Oil Drop Model Application\u2014From Globular Proteins to Amyloids. Springer Series on Bio- and Neurosystems, Springer Science and Business Media LLC.","DOI":"10.1007\/978-3-319-95843-9_19"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0022-2836(76)90004-8","article-title":"A simplified representation of protein conformations for rapid simulation of protein folding","volume":"104","author":"Levitt","year":"1976","journal-title":"J. Mol. Boil."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1214\/aoms\/1177729694","article-title":"On Information and Sufficiency","volume":"22","author":"Kullback","year":"1951","journal-title":"Ann. Math. Stat."},{"key":"ref_29","unstructured":"(2018, December 15). Available online: https:\/\/zhanglab.ccmb.med.umich.edu\/I-TASSER\/."},{"key":"ref_30","unstructured":"(2018, December 15). Available online: http:\/\/robetta.org\/submit.jsp."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Banach, M., Konieczny, L., and Roterman, I. (2019). The Amyloid as a Ribbon-Like Micelle in Contrast to Spherical Micelles Represented by Globular Proteins. Molecules, 24.","DOI":"10.3390\/molecules24234395"},{"key":"ref_32","unstructured":"Roterman-Konieczna, I. (2020). Protein is ane intelligent micelle. From Globular Proteins to Amyloids, Elsevier."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.febslet.2004.09.038","article-title":"Mutation E46K increases phospholipids binding and assembly into filaments of human alpha-synuclein","volume":"576","author":"Zibaee","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4502","DOI":"10.1039\/C7CP08321A","article-title":"The fold preference and thermodynamic stability of-synuclein fibrils is encoded in the non-amyloid-component region","volume":"20","author":"Xu","year":"2018","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.str.2013.10.020","article-title":"Predictive Atomic Resolution Descriptions of Intrinsically Disordered hTau40 and \u03b1-Synuclein in Solution from NMR and Small Angle Scattering","volume":"22","author":"Schwalbe","year":"2014","journal-title":"Structure"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"327","DOI":"10.2478\/bams-2012-0023","article-title":"Measurement of Hydrophobicity Distribution in Proteins (2012) Non-redundant Protein Data Bank","volume":"8","author":"Kalinowska","year":"2012","journal-title":"BAMS"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.neuron.2017.12.024","article-title":"\u03b1-Synuclein and Tau: Mitochondrial Kill Switches","volume":"97","author":"Pech","year":"2018","journal-title":"Neuron"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.bbamem.2017.12.011","article-title":"Membrane-induced initial structure of \u03b1-synuclein control its amyloidogenesis on model membranes","volume":"1860","author":"Terakawa","year":"2018","journal-title":"BBA-Biomembranes."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1126\/science.aan6160","article-title":"Structural basis of membrane disruption and cellular toxicity by \u03b1-synuclein oligomers","volume":"358","author":"Fusco","year":"2017","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.neulet.2017.12.001","article-title":"Suppression of autophagy in the brain of transgenic mice with overexpression of A53T-mutant \u03b1-synuclein as an early event at synucleinopathy progression","volume":"672","author":"Pupyshev","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1074\/jbc.M117.812388","article-title":"Structural features of \u03b1-synuclein amyloid fibrils revealed by Raman spectroscopy","volume":"293","author":"Flynn","year":"2017","journal-title":"J. Boil. Chem."},{"key":"ref_42","first-page":"213","article-title":"A critical review of the prion hypothesis of human synucleinopathies","volume":"373","author":"Korczyn","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00401-017-1755-1","article-title":"Alpha-synuclein oligomers: A new hope","volume":"134","author":"Roberts","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1021\/acschemneuro.7b00261","article-title":"Comparison of \u03b1-Synuclein Fibril Inhibition by Four Different Amyloid Inhibitors","volume":"8","author":"Jha","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s12551-017-0317-z","article-title":"Lessons learned from protein aggregation: Toward technological and biomedical applications","volume":"9","author":"Avila","year":"2017","journal-title":"Biophys. Rev."},{"key":"ref_46","first-page":"e55361","article-title":"Recombinant \u03b1- \u03b2- and \u03b3-Synucleins Stimulate Protein Phosphatase 2A Catalytic Subunit Activity in Cell Free Assays","volume":"126","author":"Lek","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3362","DOI":"10.1007\/s11064-017-2382-x","article-title":"The Oligomer Hypothesis in \u03b1-Synucleinopathy","volume":"42","author":"Ono","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/pro.3289","article-title":"PDBsum: Structural summaries of PDB entries","volume":"27","author":"Laskowski","year":"2017","journal-title":"Protein Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, flexible, and free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_51","unstructured":"(2018, July 05). PLGrid User Manual. Available online: https:\/\/docs.cyfronet.pl\/display\/PLGDoc\/User+manual."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ptak-Kaczor, M., Banach, M., Konieczny, L., and Roterman, I. (2019). Internal force field in selected proteins. Acta Biochim. Pol.","DOI":"10.18388\/abp.2019_2865"},{"key":"ref_53","first-page":"16","article-title":"Alzheimer\u2019s amyloid fibrils: Structure and assembly","volume":"1502","author":"Serpell","year":"2000","journal-title":"BBA-Biomembranes"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/3\/600\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:53:13Z","timestamp":1760172793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/3\/600"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,30]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["molecules25030600"],"URL":"https:\/\/doi.org\/10.3390\/molecules25030600","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,30]]}}}