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91
In Silico Prediction and Biophysical Validation of Novel 14-3-3σ Homodimer Stabilizers
Ghazi Aljabal1, Aik-Hong Teh2, Beow Keat Yap1
1School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang 11800, Malaysia.
Journal of Chemical Information and Modeling
|August 22, 2023
Summary
This study identifies peptide 3 as a stabilizer for 14-3-3σ homodimers, preventing aggregation and enhancing protein interactions. This finding offers potential therapeutic strategies for cancers where 14-3-3σ function is compromised.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- 14-3-3σ is crucial for regulating tumor metabolism and cancer cell growth but is often downregulated in cancers.
- Homodimerization of 14-3-3σ is essential for its activity, yet stabilizing these dimers remains an underexplored therapeutic avenue.
- Previous computational work suggested GCP-Lys-OMe as a potential stabilizer, but experimental validation was lacking.
Purpose of the Study:
- To computationally predict novel peptides capable of stabilizing 14-3-3σ homodimers.
- To experimentally validate the homodimer stabilizing effects of the predicted peptides.
- To investigate the impact of a lead peptide on 14-3-3σ aggregation and its interaction with other proteins.
Main Methods:
- In silico prediction of peptides using docking and molecular dynamics (MD) simulations.
- [1H]-CPMG NMR experiments to confirm peptide binding to 14-3-3σ.
- Competitive [1H]-CPMG assays and dynamic light scattering (DLS) to assess binding interactions and protein stability.
Main Results:
- Peptides 3, 5, 9, and 16 were identified as binders to 14-3-3σ, with peptide 3 exhibiting the strongest binding.
- Peptide 3 enhanced the binding of ExoS, a known 14-3-3σ binding peptide, without competing for the same site.
- Peptide 3 significantly increased the stability of 14-3-3σ homodimers against aggregation, likely by preventing monomer dissociation.
Conclusions:
- Computational methods (docking and MD simulations) are effective for identifying 14-3-3σ homodimer stabilizing compounds.
- Peptide 3 demonstrates potential as a therapeutic agent by stabilizing 14-3-3σ, preventing its aggregation, and modulating its protein interactions.
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