Stapled peptides in the p53 pathway: Computer simulations reveal novel interactions of the staples with the target protein

Stapled peptide design: principles and roles of computation

“…These additional hydrophobic interactions conferred up to a fourfold improvement in MCL-1 binding affinity compared with peptides stapled at other positions. A computational study subsequently found that a similar situation exists in a set of hydrocarbon stapled peptides that were designed to inhibit the MDM2-p53 interaction [57]. Molecular dynamics (MD) simulations of the stapled peptides complexed to MDM2 demonstrated the positive contribution to the binding free energy by staples that lie close to and interact directly with the protein surface.…”

“…Given their proximity to the protein surface, additional favourable van der Waals contacts can be formed between the partially solvent-exposed staple and protein, provided that the fit between the staple and protein surface is complimentary and no steric clash occurs. This also reduces the entropic penalty for solvating the hydrocarbon staple [57].…”

“…Simulations of the protein-peptide complex were also used in conjunction with REMD simulations of the unbound peptides to design stapled eIF4G peptides with improved binding affinities [56]. As mentioned above, MD simulations of the protein-peptide complex were also instrumental in revealing the interaction of the hydrocarbon staple of a stapled p53 peptide with the surface of MDM2 [57], which was subsequently validated by X-ray crystallography [59]. This has contributed to the important realisation that the hydrocarbon staple itself is able to contribute to target binding and should be considered in future stapled peptide designs.…”

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

“…The suggestion that phosphorylation of these sites destabilizes p53-MDM2 interaction is supported by alanine mutagenesis experiments 23 and computer simulations. 18,24,39,40 The physical rationale for the destabilization of binding is usually ascribed to thermodynamic effects 18 however, kinetic effects have not been studied in either experimental or simulation studies. In this study, we turn our attention to at least one model that describes the kinetic aspects: the structure and dynamics of the p53-MDM2 'encounter complex' before and after p53 phosphorylation.…”

Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors

“…31 In addition, the biochemical peptide interactions may be affected by stapling. 32 Some peptide-based compounds like Mifamutide, liposomal muramyl tripeptide phoshatidyl ethanolamide (MTPPE), have been used clinically as an immune system activator in the lung lesions of osteosarcoma. 33 Another successful example of using peptides to inhibit protein function requires intracellular delivery of inhibitory peptide (rPP-c8) that prevents STAT3 binding to PIAS3.…”