Despite a pioneering work of Thornton, reporting the interaction between sulfur atoms of cysteine and methionine with the aromatic rings of tryptophan, tyrosine and phenylalanine, which are nucleophiles [6], little was published in the early days of structural bioinformatics. No trace of chalcogen bonds involving methionine sulfur atoms emerged in a 1999 analysis of room-temperature protein crystal structures [7]. In a subsequent study of a larger data set, some evidence of chalcogen bonds between the methionine sulfur atom and backbone or side-chain carboxylate oxygen atoms was observed [8]. Further statistical analyses, coupled with molecular orbital ab initio calculations, confirmed that the sulfur atoms of cysteine and methionine can form chalcogen bonds with protein polar atoms [9][10]. More recently, a 2021 study showed numerous chalcogen bonds between the selenium atom of selenomethionine in low temperature protein crystal structures [11].
Ligand binding to proteins can be influenced by chalcogen bonds, too [12][13]. For example, the activity of ebselen, a glutathione peroxidase mimic, is enhanced by its ability of forming chalcogen bonds with selenium [14]. This non-bonding interaction is important also in the mechanism of inhibition of maltase glucoamylase by salacinol and katalanol [15].
In this manuscript, the chalcogen bonds that involve cysteine side-chains in proteins are identified and compared to the hydrogen bonds that involve the same side-chains, which can behave either as a hydrogen donors or as a hydrogen acceptors (Figure 1 ). This is an attempt to determine the relative energies of the two types of interactions by comparison of their frequency of occurrence.