Deciphering the Underlying Mechanism of Anion Binding by Asymmetrical Squaramide-Based Dipeptides

Anions are involved in many important processes, which has led to growing interest in designing new molecules to bind them effectively. Squaramides have gained considerable attention as effective anion receptors due to their dual hydrogen bond donor capability. Combining squaramide with biomolecules is a promising approach for designing and developing biomimetic receptors for anions with enhanced H-bonding abilities, particularly due to their functional versatility. The present study explores the mechanism of interaction of H₂PO₄^- and HSO₄^- anions with three asymmetrical squaramide-based dipeptide receptors, emphasizing the role of noncovalent interactions. The conformational states of the receptors and the amino acids of the dipeptide with varying side chain lengths are the two major factors that influence these interactions. The conformational analysis of the receptors and their anion complexes performed using conformer-rotamer ensemble sampling tool (CREST) and molecular dynamics (MD) simulations, shows that the anti/anti conformations are the most abundant. Following the MD simulations, density functional theory (DFT) was used to perform electronic structure calculations on the 1:1 receptor-anion complexes. Our findings indicate that the N-H···O and O-H···O═C interactions primarily drive the formation of the receptor-anion complexes. Energy decomposition analysis based on absolutely localized molecular orbitals (ALMO-EDA) highlighted the role of the electrostatic energy (ΔE_elst) in stabilizing the receptor-anion complexes. Further confirmation of the intermolecular N-H···O and O-H···O═C interactions in the complexes was attained through several analytic tools. This outcome lays a foundation for designing and developing more efficient and selective dipeptide-based anion receptors.