Hydrogen-bonded complexes of glycyl-l-glutamate with nucleosides: a dft and qtaim study

The complex formation between peptides and nucleosides underlies the molecular recognition and regulation processes in biological systems. The present study focuses on the optimized structures of complexes formed between the glycyl-L-glutamate and four nucleosides-adenosine, guanosine, cytidine, and uridine. The most stable structures are found for complexes in which the preferred binding sites and the relative strength of hydrogen bonds are established. The terminal charged NH₃⁺ and γ-COO^- groups, as well as the amide fragment, can act as H-bonding sites in a peptide. The functional groups NH₂, NH, CO, and N in nucleosides are potential H-bonding sites for the peptide. Unlike nucleobases, the hydroxyl groups of the ribose moiety in nucleoside molecules are additional H-bonding sites. The involvement of each of these groups depends on the complementarity of the peptide and nucleoside structures. The peptide affinity for nucleosides increases in the series: cytidine > guanosine > adenosine > uridine. The preference of each nucleoside depends on the balance of contribution from the structure rearrangement and intermolecular interaction, including electrostatic, orbital, dispersion interactions, and Pauli repulsion.

The study combines DFT/B97-D/6-311++G(3d,3p) calculations with topological (QTAIM) and energy decomposition (EDA) analyses to investigate ion-molecular complexes between the tripolar anion of glycyl-glutamic acid and the neutral nucleosides. Solvation effects were taken into account within the PCM (water) model. Several initial structures with different coordination modes were generated according to the molecular electrostatic potential (MEP) distribution. Hydrogen bond parameters were obtained from the properties of bond critical points. The interaction energies and complex formation energies were determined to estimate the stability of the systems. Energy decomposition analysis (EDA) performed using the ORCA software allowed the contributions of electrostatic, polarization, dispersion, and Pauli repulsion components to the total interaction energy to be separated.