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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Solvent effects on structural and thermochemical properties of p53 tumor-suppressor gene: a molecular modeling
Shiva Irani1, Seyed Mohammad Atyabi, Houri Mivehchi
1Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Abstract:
The p53 tumor-suppressor protein is a cellular phosphoprotein and a negative regulator of cell growth. Most p53 mutations occur in exons 5-8 within the DNA-binding domain. Therefore, p53 can potentially be targeted with novel drugs designed to bind to a mutation and restore its stability or wild-type conformation. For the current study, Hartree-Fock calculations were used to investigate the solvent-induced effects of five different solvent media (acetone, ethanol, methanol, dimethyl sulfoxide, and water) on the thermochemical parameters and relative energies, and on the multinuclear nuclear magnetic resonance shielding tensors of oxygen, nitrogen, and phosphorus nuclei, of GAT. To understand how the solvent affects the mutation region (the "hot spot") of p53, the relative energies of GAT in selected solvent media were determined. Some biological evidence suggested the structural stabilities of hot spots of GAT have the optimum temperature and solvent type for mutation. All the authors' findings are in accordance with common biological phenomena. Another important objective of this study was to compare the hydration Gibbs free energies of CUA and GAT in water using two different approaches where the solvent was treated as a continuum of the constant at different levels of Hartree-Fock theory. The Gibbs hydration energy values obtained in water with the polarized continuum model directly applied on the isolated CUA and GAT sequences were compared with those determined from the hydrated models with four, six, and eight water molecule clusters around the hot spots uracil and adenine. The clustered structures of water molecules around the hot spots of GAT (in DNA level) and CUA (in transcriptional level) were found to be energetically favored. The results of this study provide a reliable insight into the nature of mutation processes, which is of utmost importance for the study of biochemical structures, and provide a basis for drug design.
Insights
Computational chemistry reveals how solvents impact p53 protein mutation hotspots. Understanding these solvent effects on GAT and CUA structures aids in designing drugs to restore wild-type p53 conformation.
Area of Science:
- Computational chemistry
- Molecular dynamics
- Biophysics
Background:
- p53 tumor-suppressor protein regulates cell growth; mutations often occur in the DNA-binding domain.
- Targeting p53 mutations with drugs is a promising strategy for cancer therapy.
- Understanding solvent effects on mutation sites is crucial for drug design.
Purpose of the Study:
- Investigate solvent-induced effects on p53 mutation hotspots (GAT).
- Determine optimal solvent conditions for mutation site stability.
- Compare hydration energies of GAT and CUA using different computational models.
Main Methods:
- Employed Hartree-Fock calculations to study solvent effects.
- Analyzed thermochemical parameters, relative energies, and NMR shielding tensors.
- Utilized polarized continuum models and clustered water molecule approaches for hydration energy calculations.
Main Results:
- Solvent media significantly affect GAT's thermochemical parameters and relative energies.
- Clustered water molecules around GAT and CUA hotspots are energetically favored.
- Computational models provide insights into mutation processes and drug design.
Conclusions:
- Solvent choice influences the stability of p53 mutation hotspots.
- Computational methods offer valuable insights into biochemical mutations.
- Findings support the development of targeted therapies for p53-related diseases.
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