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\begin{document}

\title{Dissecting the geometric and hydrophobic constraints of stapled peptides}



\author[1]{Li Jianguo}%
\author[1]{Yaw Tan}%
\author[1]{Chandra Verma}%
\affil[1]{Agency for Science Technology and Research}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\begin{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 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 to 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 micro-environment of the binding pocket, contributing to
enhanced affinity. The dissection of the multi-facet mechanism of
hydrocarbon stapling into individual factors not only deepens
fundamental understanding of peptide stapling, but also provides
guidelines in the design of new stapled peptides.%
\end{abstract}%



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\verb`Li et al. manuscript.doc`  available at \url{https://authorea.com/users/666669/articles/667439-dissecting-the-geometric-and-hydrophobic-constraints-of-stapled-peptides}

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