Molecular model of human tropoelastin and implications of associated mutations
Protein folding poses unique challenges for large, disordered proteins due to the low resolution of structural data accessible in experiment and on the basis of short time scales and limited sampling attainable in computation. Such molecules are uniquely suited to accelerated-sampling molecular dyna...
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| Format: | Article |
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National Academy of Sciences (U.S.)
2019
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| Online Access: | http://hdl.handle.net/1721.1/120613 https://orcid.org/0000-0002-6093-031X https://orcid.org/0000-0002-4173-9659 |
| _version_ | 1826209019937685504 |
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| author | Yeo, Giselle C. Baldock, Clair Weiss, Anthony S. Tarakanova, Anna Buehler, Markus J |
| author2 | Massachusetts Institute of Technology. Department of Civil and Environmental Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Yeo, Giselle C. Baldock, Clair Weiss, Anthony S. Tarakanova, Anna Buehler, Markus J |
| author_sort | Yeo, Giselle C. |
| collection | MIT |
| description | Protein folding poses unique challenges for large, disordered proteins due to the low resolution of structural data accessible in experiment and on the basis of short time scales and limited sampling attainable in computation. Such molecules are uniquely suited to accelerated-sampling molecular dynamics algorithms due to a flat-energy landscape. We apply these methods to report here the folded structure in water from a fully extended chain of tropoelastin, a 698-amino acid molecular precursor to elastic fibers that confer elasticity and recoil to tissues, finding good agreement with experimental data. We then study a series of artificial and disease-related mutations, yielding molecular mechanisms to explain structural differences and variation in hierarchical assembly observed in experiment. The present model builds a framework for studying assembly and disease and yields critical insight into molecular mechanisms behind these processes. These results suggest that proteins with disordered regions are suitable candidates for characterization by this approach. Keywords: tropoelastin; elastic fiber; structural protein; disordered protein; molecular dynamics |
| first_indexed | 2024-09-23T14:16:24Z |
| format | Article |
| id | mit-1721.1/120613 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:16:24Z |
| publishDate | 2019 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1206132022-10-01T20:16:36Z Molecular model of human tropoelastin and implications of associated mutations Yeo, Giselle C. Baldock, Clair Weiss, Anthony S. Tarakanova, Anna Buehler, Markus J Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Tarakanova, Anna Buehler, Markus J Protein folding poses unique challenges for large, disordered proteins due to the low resolution of structural data accessible in experiment and on the basis of short time scales and limited sampling attainable in computation. Such molecules are uniquely suited to accelerated-sampling molecular dynamics algorithms due to a flat-energy landscape. We apply these methods to report here the folded structure in water from a fully extended chain of tropoelastin, a 698-amino acid molecular precursor to elastic fibers that confer elasticity and recoil to tissues, finding good agreement with experimental data. We then study a series of artificial and disease-related mutations, yielding molecular mechanisms to explain structural differences and variation in hierarchical assembly observed in experiment. The present model builds a framework for studying assembly and disease and yields critical insight into molecular mechanisms behind these processes. These results suggest that proteins with disordered regions are suitable candidates for characterization by this approach. Keywords: tropoelastin; elastic fiber; structural protein; disordered protein; molecular dynamics National Institutes of Health (U.S.) (Grant U01 HS 4976) United States. Office of Naval Research (Grant N00014-16-1-2333) 2019-03-01T19:34:28Z 2019-03-01T19:34:28Z 2018-07 2018-01 2019-02-08T18:13:41Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/120613 Tarakanova, Anna et al. “Molecular Model of Human Tropoelastin and Implications of Associated Mutations.” Proceedings of the National Academy of Sciences 115, 28 (June 2018): 7338–7343 © 2018 National Academy of Sciences https://orcid.org/0000-0002-6093-031X https://orcid.org/0000-0002-4173-9659 http://dx.doi.org/10.1073/PNAS.1801205115 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Yeo, Giselle C. Baldock, Clair Weiss, Anthony S. Tarakanova, Anna Buehler, Markus J Molecular model of human tropoelastin and implications of associated mutations |
| title | Molecular model of human tropoelastin and implications of associated mutations |
| title_full | Molecular model of human tropoelastin and implications of associated mutations |
| title_fullStr | Molecular model of human tropoelastin and implications of associated mutations |
| title_full_unstemmed | Molecular model of human tropoelastin and implications of associated mutations |
| title_short | Molecular model of human tropoelastin and implications of associated mutations |
| title_sort | molecular model of human tropoelastin and implications of associated mutations |
| url | http://hdl.handle.net/1721.1/120613 https://orcid.org/0000-0002-6093-031X https://orcid.org/0000-0002-4173-9659 |
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