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.