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p53 R175H hydrophobic patch and H-bond reorganization observed by MD simulation
Kelly M Thayer1,2, Taylor R Quinn1,3
1Department of Chemistry, Vassar College, 124 Raymond Ave, Poughkeepsie, NY, 12604.
Abstract:
Molecular dynamics simulations probe the origins of aberrant functionality of R175H p53, which normally prevent tumorigenesis. This hotspot mutation exhibits loss of its essential zinc cofactor, aggregation, and activation of gain of function promoters, characteristics contributing to the loss of normal p53 activity. This study provided molecular level insight into the reorganization of the hydrogen bonding network and the formation of a hydrophobic patch on the surface of the protein. The hydrogen bonding network globally redistributes at the expense of the stability of the β-sandwich structure, and surface residues reorganize to expose a 250 Å(2) hydrophobic patch of residues covering approximately 2% of the solvent accessible surface. These changes could both stabilize the protein in the conformation exposing the patch to solvent to mediate the reported aggregation, and cause a destabilization in the area associated with DNA binding residues to affect the specificity. The development of the patch prior to loss of zinc indicates that stabilizing the patch quickly may prevent zinc loss. Considerations for rational design of small molecule therapeutics in light of the structural insight has been discussed and it suggest the positive ring around the hydrophobic patch and conserved residues may constitute a druggable site.
Insights
The R175H p53 mutation causes cancer by disrupting protein structure and function. Molecular dynamics simulations reveal a new hydrophobic patch formation that may drive aggregation and loss of tumor suppression, offering therapeutic targets.
Area of Science:
- Molecular Biology
- Biophysics
- Computational Chemistry
Background:
- The p53 tumor suppressor protein is crucial for preventing cancer.
- The R175H mutation is a common hotspot mutation leading to aberrant p53 functionality and promoting tumorigenesis.
- Understanding the molecular basis of R175H p53 dysfunction is essential for developing targeted therapies.
Purpose of the Study:
- To investigate the molecular origins of the aberrant functionality of the R175H p53 mutation using molecular dynamics simulations.
- To elucidate the structural changes, including hydrogen bonding network reorganization and hydrophobic patch formation, associated with R175H p53 dysfunction.
- To identify potential druggable sites for therapeutic intervention.
Main Methods:
- Molecular dynamics (MD) simulations were employed to analyze the structural dynamics of R175H p53.
- Analysis focused on changes in hydrogen bonding networks, protein surface properties, and cofactor interactions.
- Computational methods were used to assess the impact of structural changes on protein stability and function.
Main Results:
- The R175H mutation leads to the loss of the essential zinc cofactor and protein aggregation.
- A significant reorganization of the hydrogen bonding network destabilizes the β-sandwich structure.
- A ~250 Å(2) hydrophobic patch is exposed on the protein surface, potentially mediating aggregation and affecting DNA binding specificity.
- Hydrophobic patch formation precedes zinc loss, suggesting it as an early event.
Conclusions:
- The R175H p53 mutation induces structural instability, leading to loss of normal function and gain of oncogenic properties.
- The formation of a surface hydrophobic patch is a key event contributing to aggregation and dysfunction.
- Targeting the identified hydrophobic patch and surrounding conserved residues presents a promising strategy for developing small molecule therapeutics against R175H p53-driven cancers.
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