Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations
The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elus...
| Autores: | , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/45265 |
| Acceso en línea: | http://hdl.handle.net/10230/45265 http://dx.doi.org/10.1038/s41598-020-69322-2 |
| Access Level: | acceso abierto |
| Palabra clave: | Intrinsically disordered proteins Peptides Proteins |
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Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulationsHerrera Nieto, Pablo, 1992-Pérez, AdriàDe Fabritiis, GianniIntrinsically disordered proteinsPeptidesProteinsThe exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elusive due to their transient nature. Molecular dynamics mitigates this limitation thanks to its capability to explore biologically relevant timescales while retaining atomistic resolution. Here, millisecond unbiased molecular dynamics simulations were performed in the exemplar N-terminal region of p53. In combination with state-of-the-art Markov state models, simulations revealed the existence of several partially ordered states accounting for [Formula: see text] 40% of the equilibrium population. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm2, as well as novel [Formula: see text]-sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins.The authors thank volunteers at GPUGRID.net for contributing with computational resources and Acellera for funding. G.D.F. acknowledges support from MINECO (Unidad de Excelencia María de Maeztu MDM-2014-0370 and BIO2017-82628-P) and FEDER. This project received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement 823712 (CompBioMed2 Project).Nature Research202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/45265http://dx.doi.org/10.1038/s41598-020-69322-2reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésSci Rep. 2020; 10(1):12402info:eu-repo/grantAgreement/EC/H2020/823712info:eu-repo/grantAgreement/ES/2PE/BIO2017-82628-P© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/452652026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| title |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| spellingShingle |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations Herrera Nieto, Pablo, 1992- Intrinsically disordered proteins Peptides Proteins |
| title_short |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| title_full |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| title_fullStr |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| title_full_unstemmed |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| title_sort |
Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations |
| dc.creator.none.fl_str_mv |
Herrera Nieto, Pablo, 1992- Pérez, Adrià De Fabritiis, Gianni |
| author |
Herrera Nieto, Pablo, 1992- |
| author_facet |
Herrera Nieto, Pablo, 1992- Pérez, Adrià De Fabritiis, Gianni |
| author_role |
author |
| author2 |
Pérez, Adrià De Fabritiis, Gianni |
| author2_role |
author author |
| dc.subject.none.fl_str_mv |
Intrinsically disordered proteins Peptides Proteins |
| topic |
Intrinsically disordered proteins Peptides Proteins |
| description |
The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elusive due to their transient nature. Molecular dynamics mitigates this limitation thanks to its capability to explore biologically relevant timescales while retaining atomistic resolution. Here, millisecond unbiased molecular dynamics simulations were performed in the exemplar N-terminal region of p53. In combination with state-of-the-art Markov state models, simulations revealed the existence of several partially ordered states accounting for [Formula: see text] 40% of the equilibrium population. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm2, as well as novel [Formula: see text]-sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins. |
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2020 |
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2020 2020 2020 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/45265 http://dx.doi.org/10.1038/s41598-020-69322-2 |
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http://hdl.handle.net/10230/45265 http://dx.doi.org/10.1038/s41598-020-69322-2 |
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Inglés |
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Inglés |
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Sci Rep. 2020; 10(1):12402 info:eu-repo/grantAgreement/EC/H2020/823712 info:eu-repo/grantAgreement/ES/2PE/BIO2017-82628-P |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
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Nature Research |
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Nature Research |
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reponame:Repositorio Digital de la UPF instname:Universitat Pompeu Fabra |
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