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Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations
Shilpa Yadahalli1,2,3,4, Jianguo Li2,5, David P Lane4
1Simons Centre for the Study of Living Machines, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bellary Road, Bangalore, 560065, India.
Scientific Reports
|November 17, 2017
Summary
The study reveals distinct binding mechanisms for p53 and 12/1 peptides to MDM2. P53 peptides primarily use conformational selection, while 12/1 peptides involve binding-induced folding, offering insights for peptide design.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- The interaction between p53 and MDM2 is crucial for regulating p53 tumor suppressor activity.
- Peptide-based inhibitors targeting the p53-MDM2 interaction are promising cancer therapeutics.
- Understanding the molecular mechanisms of peptide binding to MDM2 is essential for designing effective inhibitors.
Purpose of the Study:
- To investigate and compare the conformational landscapes and binding mechanisms of p53-derived peptides and phage-derived 12/1 peptides to MDM2.
- To elucidate the roles of conformational selection and binding-induced folding in the recognition and complexation of these peptides by MDM2.
- To propose potential modifications to 12/1 peptides to enhance their binding affinity and mechanism.
Main Methods:
- Hamiltonian replica exchange molecular dynamics (HREXMD) simulations were employed to explore the conformational dynamics of peptide-MDM2 complexes.
- Peptide-pulling simulations were conducted to analyze the dissociation pathways and energetics of the bound states.
- Analysis of simulation data provided insights into the conformational selection and binding-induced folding mechanisms.
Main Results:
- P53 peptides predominantly bind to MDM2 via the conformational selection mechanism.
- 12/1 peptides exhibit a binding mechanism that combines elements of conformational selection with significant binding-induced folding.
- Pulling simulations supported the proposed binding mechanisms and differentiated the energetic contributions.
- The findings extend previous models for the entropically driven binding of p53 peptides and enthalpically driven binding of 12/1 peptides.
Conclusions:
- The study differentiates the binding mechanisms of p53 and 12/1 peptides to MDM2, highlighting conformational selection for p53 and binding-induced folding for 12/1 peptides.
- The proposed mechanisms provide a framework for understanding the entropic and enthalpic drivers of peptide-MDM2 interactions.
- The findings suggest strategies for rational design of novel peptide inhibitors by modulating helicity and binding mechanisms, potentially leading to improved therapeutic agents.
