Molecular Rewiring of Tetrapeptides: Exploring the Role of Backbone Esterification in Anion Binding

Understanding the interactions between biomolecules and anions is crucial in biochemistry and environmental science. Depsipeptide, a peptide analogue in which one or more amide bonds are replaced with ester linkages, provides greater flexibility and altered binding properties compared to regular peptides. In this study, we explored a glycine-based tetradepsipeptide as a receptor for dihydrogen phosphate (H2PO4-) and hydrogen sulfate (HSO4-) using conformational sampling, molecular dynamics simulations, and electronic structure calculations in both gas and aqueous phases. The position of ester linkages was found to influence the geometry and energetics of binding. Hydrogen bonding interactions such as O─H···O═C and N─H···O were the main driving force that stabilized the receptor-anion complexes, as supported by the noncovalent interaction (NCI) index. In solution, water molecules compete with the receptor for anion binding, thereby influencing both the interaction strength and the geometry of the complexes. These results show that ester substitution in peptide backbones can be a useful strategy for designing effective peptide-based anion receptors.