Halogen bonding in complexes of proteins and non-natural amino acids

In this work, we have analyzed the influence of halogen bonding to the stability of 44 complexes of proteins and non-natural amino acids. Fluorine- and chlorine-containing non-natural amino acids are more prevalent in the dataset, and an even larger number of contacts made by iodine-containing ligands are found. Only few halogen bonds with the hydroxyl oxygens and carboxylate side chains are found in the dataset. Halogen bonds with the nitrogen-containing side chains have higher occurrence than other acceptors. Backbone carbonyl oxygens and nitrogens are to a substantial extent involved in our dataset. We have observed a small percentage of interactions involving water as hydrogen bond donors. Additionally, most of the interacting residues comprising the interfaces also show a great degree of conservation. There is a clear interaction hot spot at distances of 3.5–3.7 Å and Θ₁ angles of 100–120°. There is also a cluster of contacts featuring short distances (2.6–2.9 Å) but only nearly optimal Θ₁ angles (140–160°). 51.3% of stabilizing residues are involved in building halogen bonds with the non-natural amino acids. We discovered three types of structural motifs significantly over-represented: beta-turn-ir, beta-turn-il and niche-4r. The halogen-bonding statistics of the dataset do not show any preference for α-helices (36%), β-sheets (36%), or turns/coils (28%) structures. Most of the amino acid residues that were involved in halogen bonds prefer to be in the solvent excluded environment (buried). Furthermore, we have shown that in amino acid–protein complexes halogen atoms can sometimes be involved in hydrogen bonding interactions with hydrogen bonding-donors. The results from this study might be used for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.