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Published on: January 5, 2024
Effect of linker on the binding free energy of stapled p53/HDM2 complex
1Department of Chemistry, The Research Institute of Natural Sciences, Sookmyung Women's University, Seoul, Korea.
Abstract:
Inactivation of the tumor suppressor p53 resulting from the binding with a negative regulator HDM2 is among the predominant defects in human cancers. p53-mimicking peptides whose conformational and proteolytic stability is enhanced by an all-hydrocarbon staple are being recognized as promising anticancer agents for disrupting the p53-HDM2 binding and reactivating p53. Herein, we conduct a computational modeling and thermodynamic characterization of stapled p53/HDM2 complex via molecular docking, simulations, and binding free energy analysis. The binding thermodynamics analysis is done based on the end-point calculation of the effective binding energy-a sum of the direct peptide-protein interaction energy and the dehydration penalty-and on its decomposition into contributions from specific groups constituting the complex. This allows us to investigate how individual amino acids in the stapled p53 and HDM2 contribute to the binding affinity. We find that not only the epitope residues (F19, W23 and L26), but also the hydrocarbon linker of the stapled p53 impart significant contributions. Our computational approach will be useful in designing new stapled peptides in which the staple location is also optimized to improve the binding affinity.
Insights
Stapled peptides that mimic tumor suppressor p53 show promise for cancer treatment by disrupting p53-HDM2 binding. Computational analysis reveals key contributions from both peptide residues and the hydrocarbon staple to binding affinity.
Area of Science:
- Biochemistry
- Computational Biology
- Oncology
Background:
- Inactivation of tumor suppressor p53 by HDM2 is a common defect in human cancers.
- Stapled p53-mimicking peptides offer a strategy to disrupt p53-HDM2 binding and restore p53 function.
- These peptides possess enhanced conformational and proteolytic stability.
Purpose of the Study:
- To computationally model and thermodynamically characterize the stapled p53/HDM2 complex.
- To investigate the contributions of individual amino acids and the hydrocarbon linker to binding affinity.
- To guide the design of novel stapled peptides with improved binding affinity.
Main Methods:
- Molecular docking simulations were employed to model the stapled p53/HDM2 complex.
- Binding free energy analysis was performed using end-point calculations.
- Decomposition of binding energy into group contributions identified key interacting residues and the staple linker.
Main Results:
- Both epitope residues (F19, W23, L26) and the hydrocarbon staple of the stapled p53 significantly contribute to binding affinity.
- The computational approach successfully characterized the thermodynamic contributions to binding.
- Specific amino acid residues and the staple linker were identified as critical for high-affinity binding.
Conclusions:
- Computational modeling provides valuable insights into the binding interactions of stapled p53 peptides with HDM2.
- The hydrocarbon staple plays a crucial role in enhancing the binding affinity of p53-mimicking peptides.
- This approach can facilitate the rational design of more effective stapled peptide anticancer agents by optimizing staple placement.
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