Characterization of Protein–Ligand Chalcogen Bonds: Insights from Database Survey and Quantum Mechanics Calculations

Chalcogen bonds (ChBs) are essential noncovalent interactions in biological systems and drug molecules, playing a key role in stabilizing protein structures and determining the bound conformations of drugs. While previous studies on ChBs in biological systems have primarily focused on interactions between residues and within drug molecules, systematic investigations into the characteristics of ChBs between proteins and ligands remain limited. This study systematically explores ChBs between proteins and sulfur-containing ligands using comprehensive database analyses and precise quantum mechanics (QM) calculations. The findings reveal the persistent prevalence of sulfur throughout the drug development process, underscoring the importance of considering sulfur's role in fragment-based drug design. A survey of the Protein Data Bank (PDB) identified specific preferences in distance, angle, and backbone/side chain interactions for ChBs within protein-ligand complexes, offering valuable insights for structure-based drug design. Furthermore, QM calculations demonstrate that protein-ligand ChBs are characterized by electrostatic complementarity, dispersion, and inter/intramolecular charge transfer. This systematic investigation substantially advances our understanding of protein-ligand ChBs in biological systems.