Chalcogen bond interactions involving sulphur atoms of methionine or cysteine residues and backbone carbonyl oxygen atoms in protein structures

Abstract

Chalcogen bonds (ChBs) are attractive non-covalent interactions that occur between group 16 elements and nucleophiles, and many studies have investigated ChBs in various chemical systems. The strength and significance of ChBs in biological systems are yet to be clearly elucidated. In this study, we investigated ChBs between the sulphur atoms of Cys/Met and the backbone carbonyl oxygen atoms in ∼5600 high-resolution protein structures. We identified 1241 and 2796 examples of ChBs in Cys and Met that satisfied our geometric criteria. We selected a subset of these examples for further characterization, in which the distance between the sulphur and the oxygen atoms for the interacting residues is the minimum. We performed quantum chemical calculations on the model compounds using MP2 and density functional theory (DFT) with and without dispersion correction (PBE-03, DFT-D3 and DFT B3LYP). Our calculations show that the most favorable interaction energies are in the range of −1.1 to −1.2 kcal mol⁻¹ in dispersion-corrected DFT calculations. The interaction energies of the majority of the model compounds in DFT B3LYP calculations are not favorable, indicating the significance of dispersion interactions. A significant number of ChBs occur in α-helices and β-strands and ChBs are likely to stabilize the association of secondary structural elements in protein structures. Our studies indicate that the strength of S⋯OC ChBs investigated in this study is comparable to weak interactions such as C–H⋯O hydrogen bonds and they are likely to play a significant role in protein folding, protein stability and protein–drug interactions. Further mutation and functional studies are required to clearly ascertain the role of ChBs in proteins.