Microscopic Insights into the Solvation of Stapled Peptides-A Case Study of p53-MDM2

Water, often termed the universal solvent, plays a vital role in numerous biomolecular processes, including protein-protein interactions. These interactions are frequently mediated by water molecules, making their characterization essential for developing therapeutic strategies. One such critical complex is p53-MDM2, which is central to cellular regulation. Inhibiting the p53-MDM2 interaction remains a significant therapeutic challenge, and stapled peptides have emerged as promising candidates in this context. The stapled peptides are peptidomimetics in which the side chains of two suitably positioned amino acids are covalently linked using an appropriate chemical moiety. In this study, we investigate the role of water in the binding of stapled p53 peptides to MDM2 using extensive molecular dynamics simulations. Our aim is to understand how variations in the chemical nature and stapling position of the hydrocarbon cross-linker influence the behavior of water molecules surrounding the p53 peptide. We demonstrate that such modifications significantly alter the structure and dynamics of the surrounding solvent. Using rigorous entropy calculations, we rationalize the enhanced binding affinity of stapled p53 peptides compared to that of their unstapled counterparts from a solvent-centric perspective. Specifically, the entropy gain of water molecules around the stapled peptides, combined with the conformational entropy loss of the peptide, contributes favorably to binding. These findings offer valuable insights into the rational design of stapled peptides and support the development of improved therapeutic inhibitors targeting the p53-MDM2 interaction.