Mechanism of Stapled Peptide Binding to MDM2: Possible Consequences for Peptide Design

Abstract

MDM2 is a negative regulator of p53. The N terminal domain of MDM2 interacts with a helical region of the transcriptional activation domain of p53. Stapled peptides have been designed to mimic this interaction, in order to inhibit p53-MDM2 binding and thereby activate the p53 response. Here, we studied how the helical segment of p53 or a stapled peptide (re)binds to MDM2 as it is systematically displaced from the MDM2 binding pocket. Depending on its sequence, presence of staple, and/or a C-terminal tail, the peptide approaches MDM2 differently and not exclusively via the crack propagation mechanism proposed previously for p53. The presence of an interacting staple appears to reduce the peptide's sensitivity to mutations of key hydrophobic residues of p53, and this could pave the way for increased diversity in sequence design of stapled peptides used in inhibiting the p53-MDM2 interaction. We further found that the presence of a hydrophobic staple in the peptide-MDM2 interface tends to trap a network of water molecules prior to binding. The release of these structured waters would then reduce the entropic penalty upon peptide binding.

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

“…The highest peaks were observed for two protein-peptide contacts: Gly58-Phe19 and Gln72-Phe19. p53 residue Phe19 is often reported as crucial for the p53-MDM2 interaction in experimental studies49505152. Its importance is also visible in our simulation results as a distinct contact frequency peak in Fig.…”

“…Out of those, Leu54, Gly58, Ile61, Met62, Tyr67, His96, Ile99, Tyr100 have been identified as the most important according to experimental studies15324647484950. In our simulations, we observed the highest contact frequencies for the residues: Gly58, Met62, Gln72, His96 and increased frequencies for their neighbors (as indicated in the histogram in Fig.…”

Stapled peptide design: principles and roles of computation

“…Multiple short approach simulations were performed for a range of peptide-protein distances on a set of wild-type, unstapled, and stapled p53 peptides, to study the effect of the hydrocarbon staple on the mechanism of peptide binding [85]. The peptide set featured those with staples that associate with the MDM2 protein surface in the complex.…”

P53 and Murine Double Mimute 2 (MDM2) Expression Changes and Significance in Different Types of Endometrial Lesions

“…It participates in regulating cell cycle and promoting cell proliferation, thus facilitating tumor growth [22,23]. However, little is known about MDM2 expression in various endometrial lesions, including uterine adenomyosis, endometrial polyps, and endometrial carcinoma.…”