In this study**, the effects of water and solvation on the alpha-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 alpha-helix structure in water. The binding affinity calculations by WaterMap provided over one hundred hydration sites in the 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 experimental data, potential of mean forces by weighted histogram analysis methods indicated the order of peptides from lowest to highest binding affinity. Our study provided a comprehensive rationalization of the relationship between peptide stapling strategy, the secondary structural stability, and the binding affinity of p53/MDM2 complex.** Chemical Biology & Drug Design (in press; 2014). In collaboration with Z. Guo, K. Streu, and G. Krilov. UM acknowledges a John Simon Guggenheim Memorial fellowship.

Probing the origin of structural stability of single and double stapled p53 peptide analogs bound to MDM2: Effects of water and solvation

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.