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Exploring the Functional Landscape of the p53 Regulatory Domain : The Stabilizing Role of Post-Translational Modifications

Bakker, Michael J. LU ; Svensson, Oskar LU ; So̷rensen, Henrik V. LU and Skepö, Marie LU (2024) In Journal of Chemical Theory and Computation 20(14). p.5842-5853
Abstract

This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our... (More)

This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our model system is the regulatory domain p53 of the tumor suppressor protein p53, this study contributes to understanding the general effects of intrinsically disordered phosphorylated proteins and the impact of phosphorylated groups, more specifically, how minor changes in the primary sequence can affect the properties mentioned above.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
20
issue
14
pages
12 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38973087
  • scopus:85198185034
ISSN
1549-9618
DOI
10.1021/acs.jctc.4c00570
language
English
LU publication?
yes
id
14bb0987-0c29-413e-badc-9f58b3fab301
date added to LUP
2024-09-13 14:54:01
date last changed
2024-10-11 19:44:42
@article{14bb0987-0c29-413e-badc-9f58b3fab301,
  abstract     = {{<p>This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our model system is the regulatory domain p53 of the tumor suppressor protein p53, this study contributes to understanding the general effects of intrinsically disordered phosphorylated proteins and the impact of phosphorylated groups, more specifically, how minor changes in the primary sequence can affect the properties mentioned above.</p>}},
  author       = {{Bakker, Michael J. and Svensson, Oskar and So̷rensen, Henrik V. and Skepö, Marie}},
  issn         = {{1549-9618}},
  language     = {{eng}},
  number       = {{14}},
  pages        = {{5842--5853}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Chemical Theory and Computation}},
  title        = {{Exploring the Functional Landscape of the p53 Regulatory Domain : The Stabilizing Role of Post-Translational Modifications}},
  url          = {{http://dx.doi.org/10.1021/acs.jctc.4c00570}},
  doi          = {{10.1021/acs.jctc.4c00570}},
  volume       = {{20}},
  year         = {{2024}},
}