Understanding the p53-MDM2 Binding/Unbinding Mechanism via Molecular Dynamics and Free Energy Calculations

In fifteen words or less, explain the significance of this contribution (Novel Aspect).: Elucidating p53-MDM2 dynamics advances targeted cancer therapy by revealing key binding and inhibition mechanisms

Abstract Text:

The tumor suppressor protein p53 plays a key role in cancer prevention by regulating DNA repair, apoptosis, and cell cycle arrest.  Its activity is tightly regulated by MDM2, which binds to p53’s N-terminal transactivation domain and promotes its degradation. However, MDM2 overexpression can lead to excessive p53 inhibition, allowing uncontrolled cell proliferation and tumor development.

To gain the mechanistic insights into this crucial interaction, an important target for anticancer therapies, we investigated the binding and unbinding pathways of p53-MDM2 complex using the crystal structure having the PDB ID: 1YCR.  We employed Molecular Dynamics (MD) simulations along with Umbrella Sampling (US) to characterize this process. The energetic barriers associated with unbinding trajectories along the x, y, and z directions were estimated using potential of mean force (PMF) calculations. 

We further examined the structural dynamics and stability of p53 upon separation from MDM2 through hydrogen bond analysis and quantified the interaction thermodynamics using MM/PBSA and MM/GBSA calculations. In addition, we explored the impact of p53 mutations on MDM2 binding affinity using p53-mimicking peptides. Finally, we assessed the influence of potential MDM2 inhibitors on the p53-MDM2 interactions by evaluating RMSD, RMSF, and dissociation energy of the complexes.