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Exploring the Role of Globular Domain Locations on an Intrinsically Disordered Region of p53 : A Molecular Dynamics Investigation

Bakker, Michael J. LU ; Sørensen, Henrik V. LU and Skepö, Marie LU (2023) In Journal of Chemical Theory and Computation
Abstract

The pre-tetramerization loop (PTL) of the human tumor suppressor protein p53 is an intrinsically disordered region (IDR) necessary for the tetramerization process, and its flexibility contributes to the essential conformational changes needed. Although the IDR can be accurately simulated in the traditional manner of molecular dynamics (MD) with the end-to-end distance (EEdist) unhindered, we sought to explore the effects of restraining the EEdist to the values predicted by electron microscopy (EM) and other distances. Simulating the PTL trajectory with a restrained EEdist , we found an increased agreement of nuclear magnetic resonance (NMR) chemical shifts with experiments. Additionally, we observed a... (More)

The pre-tetramerization loop (PTL) of the human tumor suppressor protein p53 is an intrinsically disordered region (IDR) necessary for the tetramerization process, and its flexibility contributes to the essential conformational changes needed. Although the IDR can be accurately simulated in the traditional manner of molecular dynamics (MD) with the end-to-end distance (EEdist) unhindered, we sought to explore the effects of restraining the EEdist to the values predicted by electron microscopy (EM) and other distances. Simulating the PTL trajectory with a restrained EEdist , we found an increased agreement of nuclear magnetic resonance (NMR) chemical shifts with experiments. Additionally, we observed a plethora of secondary structures and contacts that only appear when the trajectory is restrained. Our findings expand the understanding of the tetramerization of p53 and provide insight into how mutations could make the protein impotent. In particular, our findings demonstrate the importance of restraining the EEdist in studying IDRs and how their conformations change under different conditions. Our results provide a better understanding of the PTL and the conformational dynamics of IDRs in general, which are useful for further studies regarding mutations and their effects on the activity of p53.

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Journal of Chemical Theory and Computation
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:38230670
  • scopus:85183495090
ISSN
1549-9618
DOI
10.1021/acs.jctc.3c00971
language
English
LU publication?
yes
id
83ac6879-f925-43b4-b9f7-667557dc71ff
date added to LUP
2024-02-15 15:44:07
date last changed
2024-04-16 14:49:27
@article{83ac6879-f925-43b4-b9f7-667557dc71ff,
  abstract     = {{<p>The pre-tetramerization loop (PTL) of the human tumor suppressor protein p53 is an intrinsically disordered region (IDR) necessary for the tetramerization process, and its flexibility contributes to the essential conformational changes needed. Although the IDR can be accurately simulated in the traditional manner of molecular dynamics (MD) with the end-to-end distance (EE<sub>dist</sub>) unhindered, we sought to explore the effects of restraining the EE<sub>dist</sub> to the values predicted by electron microscopy (EM) and other distances. Simulating the PTL trajectory with a restrained EE<sub>dist</sub> , we found an increased agreement of nuclear magnetic resonance (NMR) chemical shifts with experiments. Additionally, we observed a plethora of secondary structures and contacts that only appear when the trajectory is restrained. Our findings expand the understanding of the tetramerization of p53 and provide insight into how mutations could make the protein impotent. In particular, our findings demonstrate the importance of restraining the EE<sub>dist</sub> in studying IDRs and how their conformations change under different conditions. Our results provide a better understanding of the PTL and the conformational dynamics of IDRs in general, which are useful for further studies regarding mutations and their effects on the activity of p53.</p>}},
  author       = {{Bakker, Michael J. and Sørensen, Henrik V. and Skepö, Marie}},
  issn         = {{1549-9618}},
  language     = {{eng}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Chemical Theory and Computation}},
  title        = {{Exploring the Role of Globular Domain Locations on an Intrinsically Disordered Region of p53 : A Molecular Dynamics Investigation}},
  url          = {{http://dx.doi.org/10.1021/acs.jctc.3c00971}},
  doi          = {{10.1021/acs.jctc.3c00971}},
  year         = {{2023}},
}