Empowering canonical biochemicals with cross‐linked novelty: Recursions in applications of protein cross‐links

Diversity in the biochemical workhorses of the cell—that is, proteins—is achieved by the innumerable permutations offered primarily by the 20 canonical L‐amino acids prevalent in all biological systems. Yet, proteins are known to additionally undergo unusual modifications for specialized functions. Of the various post‐translational modifications known to occur in proteins, the recently identified non‐disulfide cross‐links are unique, residue‐specific covalent modifications that confer additional structural stability and unique functional characteristics to these biomolecules. We review an exclusive class of amino acid cross‐links encompassing aromatic and sulfur‐containing side chains, which not only confer superior biochemical characteristics to the protein but also possess additional spectroscopic features that can be exploited as novel chromophores. Studies of their in vivo reaction mechanism have facilitated their specialized in vitro applications in hydrogels and protein anchoring in monolayer chips. Furthering the discovery of unique canonical cross‐links through new chemical, structural, and bioinformatics tools will catalyze the development of protein‐specific hyperstable nanostructures, superfoods, and biotherapeutics.