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Photo Marie Skepö

Marie Skepö

Professor

Photo Marie Skepö

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

Author

  • Michael J. Bakker
  • Henrik V. Sørensen
  • Marie Skepö

Summary, in English

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.

Department/s

  • Computational Chemistry
  • MAX IV, Diffraction and scattering
  • LU Profile Area: Light and Materials
  • Department of Chemistry
  • LTH Profile Area: Nanoscience and Semiconductor Technology
  • NanoLund: Centre for Nanoscience
  • eSSENCE: The e-Science Collaboration
  • LINXS - Institute of advanced Neutron and X-ray Science

Publishing year

2024

Language

English

Pages

1423-1433

Publication/Series

Journal of Chemical Theory and Computation

Volume

20

Issue

3

Document type

Journal article

Publisher

The American Chemical Society (ACS)

Topic

  • Theoretical Chemistry (including Computational Chemistry)

Status

Published

ISBN/ISSN/Other

  • ISSN: 1549-9618