Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations

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• dc.contributor.author Herrera Nieto, Pablo, 1992-
• dc.contributor.author Pérez, Adrià
• dc.contributor.author De Fabritiis, Gianni
• dc.date.accessioned 2020-09-08T06:55:45Z
• dc.date.available 2020-09-08T06:55:45Z
• dc.date.issued 2020
• dc.description.abstract 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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Herrera-Nieto P, Pérez A, De Fabritiis G. Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations. Sci Rep. 2020; 10(1):12402. DOI: 10.1038/s41598-020-69322-2
• dc.identifier.doi http://dx.doi.org/10.1038/s41598-020-69322-2
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/45265
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Sci Rep. 2020; 10(1):12402
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/823712
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-82628-P
• dc.rights © 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/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Intrinsically disordered proteins
• dc.subject.keyword Peptides
• dc.subject.keyword Proteins
• dc.title Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion