Probing the Origin of Structural Stability of Single and Double Stapled p53 Peptide Analogs Bound to MDM2

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Abstract

The stabilization of secondary structure is believed to play an important role in the peptide–protein binding interaction. In this study, the α-helical conformation and structural stability of single and double stapled all-hydrocarbon cross-linked p53 peptides when bound and unbound to MDM2 are investigated. We determined the effects of the peptide sequence, the stereochemistry of the cross-linker, the conformation of the double bond in the alkene bridge, and the length of the bridge, to the relative stability of the α-helix structure. The binding affinity calculations by WaterMap provided over one hundred hydration sites in the MDM2 binding pocket where water density is greater than twice that of the bulk, and the relative value of free energy released by displacing these hydration sites. In agreement with the experimental data, potentials of mean force obtained by weighted histogram analysis methods indicated the order of peptides from lowest to highest binding affinity. Our study provides a comprehensive rationalization of the relationship between peptide stapling strategy, the secondary structural stability, and the binding affinity of p53/MDM2 complex. We hope our efforts can help to further the development of a new generation p53/MDM2 inhibitors that can reactivate the function of p53 as tumor suppressor gene.

The conformation and structural stability of single and double stapled all-hydrocarbon cross-linked p53 peptides in solution and when bound to MDM2 are investigated. The free energy released by displacing the hydration sites populating the staple binding pocket was determined. The order of the peptides from lowest to highest binding affinity as determined by the potential of mean forces and weighted histogram analysis methods is in agreement with the experimental data.

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