title: Probing the origin of structural stability of single and double stapled p53 peptide analogs bound to MDM2.
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.
authors.affiliation: Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, MA, 02467, USA; Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr., San Diego, CA, 92121, USA.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Guo
authors.forename: Kristina
authors.initials: K
authors.lastname: Streu
authors.forename: Goran
authors.initials: G
authors.lastname: Krilov
authors.forename: Udayan
authors.initials: U
authors.lastname: Mohanty
mesh_terms: D056004:Molecular Dynamics Simulation; D015335:Molecular Probes; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015335:Molecular Probes; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: WaterMap; conformation population; contact map; end-to-end distance; native contact; potential of mean forces; stapled peptide