Effect of Stapling on the Thermodynamics of mdm2–p53 Binding

Protein–protein interaction
(PPI) is one of the key regulatory
features driving biomolecular processes and hence is targeted for
designing therapeutics against diseases. Small peptides are a new
and emerging class of therapeutics owing to their high specificity
and low toxicity. For achieving efficient targeting of the PPI, amino
acid side chains are often stapled together, resulting in the rigidification
of these peptides. Exploring the scope of these peptides demands a
comprehensive understanding of their working principle. In this work,
two stapled p53 peptides have been considered to delineate their binding
mechanism with mdm2 using computational approaches. The addition of
stapling agent protects the secondary structure of the peptides even
in the case of thermal and chemical denaturation. Although the introduction
of a stapling agent increases the hydrophobicity of the peptide, the
enthalpic stabilization decreases. This is overcome by the lowering
of the entropic penalty, and the overall binding affinity improves.
The mechanistic insights into the benefit of peptide stapling can
be adopted for further improvement of peptide therapeutics.