Exploring the Functional Landscape of the p53 Regulatory Domain : The Stabilizing Role of Post-Translational Modifications
(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
- Bakker, Michael J. LU ; Svensson, Oskar LU ; So̷rensen, Henrik V. LU and Skepö, Marie LU
- organization
-
- Computational Chemistry
- LU Profile Area: Light and Materials
- MAX IV Laboratory
- MAX IV, Diffraction and scattering
- NanoLund: Centre for Nanoscience
- eSSENCE: The e-Science Collaboration
- LTH Profile Area: Nanoscience and Semiconductor Technology
- LUNARC, Centre for Scientific and Technical Computing at Lund University
- publishing date
- 2024-07
- 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}}, }