Investigation of S···O Chalcogen-Bond Interaction: A Combined Protein Data Bank Survey and Theoretical Calculations

Abstract

Sulfur-containing heterocycles such as thiophene, thiazole, and thiadiazole frequently appear in biologically active molecules, although the intrinsic nature of their S···O chalcogen-bonding (ChB) interactions in protein–ligand complexes is yet to be completely understood. In this work, a comprehensive survey of the Protein Data Bank (December 2024 release) was carried out, identifying more than 3,000 crystal structures in which these heterocycles engage in chalcogen-bonding interaction. Among those, 1547 unique structures show S···O close contacts with the oxygen atom of the protein carbonyl group and/or side chain. Statistical analysis of distance and angular distributions reveals distinct interaction preferences across the three heterocyclic families. Representative complexes were examined using truncated structures, enabling comparison between crystallographic geometries and optimized gas-phase structures. Quantum chemical calculations, including AIM, NBO, ESP, and EDA analyses, show that electron-withdrawing substituents enhance the stability of S···O ChB interaction by increasing the positive potential on sulfur and lowering the energy of the${\sigma }_{C-S}^{*}$orbital (LUMO). Thiadiazoles exhibit the strongest intrinsic ChB ability, followed by thiazoles and thiophenes. Together, these results provide a detailed molecular-level understanding of S···O ChB interaction and insights into the structural and energetic factors governing the interaction of sulfur-containing ligands within protein environments.