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Title: Characterizing the conformational landscape of MDM2-binding p53 peptides using molecular dynamics simulations
Authors: Yadahalli, Shilpa
Li, Jianguo
Lane, David P.
Gosavi, Shachi
Verma, Chandra Shekhar
Keywords: Computational Biology and Bioinformatics
Drug Discovery
Issue Date: 2017
Source: Yadahalli, S., Li, J., Lane, D. P., Gosavi, S., & Verma, C. S. (2017). Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations. Scientific Reports, 7(1), 15600-.
Series/Report no.: Scientific Reports
Abstract: The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’. This hypothesis is further supported by pulling simulations that pull the peptides away from their bound states with MDM2. This data extends the earlier mechanisms proposed to rationalize the entropically driven binding of the p53 set and the enthalpically driven binding of the 12/1 set. Using our hypothesis, we suggest mutations to the 12/1 peptide that increase its helicity in simulations and may, in turn, shift the binding towards conformational selection. In summary, understanding the conformational landscapes of the MDM2-binding peptides may suggest new peptide designs with bespoke binding mechanisms.
ISSN: 2045-2322
DOI: 10.1038/s41598-017-15930-4
Rights: © 2017 The Author(s). 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. Te 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
Fulltext Permission: open
Fulltext Availability: With Fulltext
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