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Probing the Origin of Structural Stability of Single and Double Stapled p53 Peptide Analogs Bound to MDM 2
Author(s) -
Guo Zuojun,
Streu Kristina,
Krilov Goran,
Mohanty Udayan
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12284
Subject(s) - peptide , chemistry , linker , stereochemistry , binding energy , structural stability , binding site , crystallography , biophysics , biochemistry , biology , physics , structural engineering , computer science , nuclear physics , engineering , operating system
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 MDM 2 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 MDM 2 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/ MDM 2 complex. We hope our efforts can help to further the development of a new generation p53/ MDM 2 inhibitors that can reactivate the function of p53 as tumor suppressor gene.