Li, J., Tan, Y. S., & Verma, C. S. (2024). Dissecting the geometric and hydrophobic constraints of stapled peptides. Proteins: Structure, Function, and Bioinformatics, 93(1), 287–301. Portico. https://doi.org/10.1002/prot.26662
Abstract:
Stapled peptides are a promising class of molecules with potential as highly specific probes of protein–protein interactions and as therapeutics. Hydrocarbon stapling affects the peptide properties through the interplay of two factors: enhancing the overall hydrophobicity and constraining the conformational flexibility. By constructing a series of virtual peptides, we study the role of each factor in modulating the structural properties of a hydrocarbon‐stapled peptide PM2, which has been shown to enter cells, engage its target Mouse Double Minute 2 (MDM2), and activate p53. Hamiltonian replica exchange molecular dynamics (HREMD) simulations suggest that hydrocarbon stapling favors helical populations of PM2 through a combination of the geometric constraints and the enhanced hydrophobicity of the peptide. To further understand the conformational landscape of the stapled peptides along the binding pathway, we performed HREMD simulations by restraining the peptide at different distances from MDM2. When the peptide approaches MDM2, the binding pocket undergoes dehydration which appears to be greater in the presence of the stapled peptide compared with the linear peptide. In the binding pocket, the helicity of the stapled peptide is increased due to the favorable interactions between the peptide residues as well as the staple and the microenvironment of the binding pocket, contributing to enhanced affinity. The dissection of the multifaceted mechanism of hydrocarbon stapling into individual factors not only deepens fundamental understanding of peptide stapling, but also provides guidelines for the design of new stapled peptides.
License type:
Publisher Copyright
Funding Info:
This research is supported by core funding from: A*STAR - Bioinformatics Institute (BII).
Description:
This is the peer reviewed version of the following article: Li, J., Tan, Y. S., & Verma, C. S. (2024). Dissecting the geometric and hydrophobic constraints of stapled peptides. Proteins: Structure, Function, and Bioinformatics, 93(1), 287–301. Portico. https://doi.org/10.1002/prot.26662
, which has been published in final form at https://doi.org/10.1002/prot.26662. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.