Self-contacts in Asx and Glx residues of high-resolution protein structures: Role of local environment and tertiary interactions

In protein structures, side-chains of asparagine and aspartic acid (Asx) and glutamine and glutamic acid (Glx) can approach their own backbone nitrogen or carbonyl group. We have systematically analyzed intra-residue contacts in Asx and Glx residues and their secondary structure preferences in two different datasets consisting of 500 and 1506 high-resolution structures. Intra-residue contact in an Asx/Glx residue between the heavy atoms of side-chain and main-chain functional groups of the same residue was investigated irrespective of whether such contacts are due to hydrogen bonding or not. Our search yielded 563 and 1462 cases of self-contacting Asx and Glx residues from the two datasets. Two important observations have been made in this analysis. First, self-contacts involving side-chain oxygen and backbone nitrogen atoms in majority of Asx residues are not due to hydrogen bonds. In the second instance, surprisingly, side-chain and backbone carbonyl oxygens of a significant number of Asx and Glx residues approach each other. For a wide-range of accessible surface areas, self-contacting residues are surrounded by less number of polar groups compared to all other Asx/Glx residues. In buried and partially buried regions, side-chain and main-chain functional groups of these residues together participate in simultaneous interactions with the available polar groups or water molecules. Asx/Glx residues with self-contacts are rarely observed in the middle of an α-helix or a β-strand. Asx/Glx side-chain having contact with its own backbone nitrogen shows different capping preferences compared to those having contact with its backbone oxygen. Examples of proteins with multiple self-contacting Asx/Glx residues are found. We speculate that mutation of a self-contacting residue in the buried or partially buried region of a protein will destabilize the structure. The results of this analysis will help in engineering protein structures and site-directed mutagenesis experiments.