Prediction of functionally important residues in globular proteins from unusual central distances of amino acids

Abstract

BackgroundWell-performing automated protein function recognition approaches usually comprise several complementary techniques. Beside constructing better consensus, their predictive power can be improved by either adding or refining independent modules that explore orthogonal features of proteins. In this work, we demonstrated how the exploration of global atomic distributions can be used to indicate functionally important residues.ResultsUsing a set of carefully selected globular proteins, we parametrized continuous probability density functions describing preferred central distances of individual protein atoms. Relative preferred burials were estimated using mixture models of radial density functions dependent on the amino acid composition of a protein under consideration. The unexpectedness of extraordinary locations of atoms was evaluated in the information-theoretic manner and used directly for the identification of key amino acids. In the validation study, we tested capabilities of a tool built upon our approach, called SurpResi, by searching for binding sites interacting with ligands. The tool indicated multiple candidate sites achieving success rates comparable to several geometric methods. We also showed that the unexpectedness is a property of regions involved in protein-protein interactions, and thus can be used for the ranking of protein docking predictions. The computational approach implemented in this work is freely available via a Web interface at http://www.bioinformatics.org/surpresi.ConclusionsProbabilistic analysis of atomic central distances in globular proteins is capable of capturing distinct orientational preferences of amino acids as resulting from different sizes, charges and hydrophobic characters of their side chains. When idealized spatial preferences can be inferred from the sole amino acid composition of a protein, residues located in hydrophobically unfavorable environments can be easily detected. Such residues turn out to be often directly involved in binding ligands or interfacing with other proteins.

Methionine Sulfoxide Reductases Preferentially Reduce Unfolded Oxidized Proteins and Protect Cells from Oxidative Protein Unfolding

“…Therefore, the high content of aromatic and aliphatic residues in MSRs could be an important factor promoting the ability of these enzymes to preferentially use unfolded protein substrates through hydrophobic or -stacking interactions. This property should allow them to exhibit a higher affinity for hydrophobic regions of target proteins, such as protein cores and regions involved in protein-protein interactions through hydrophobic interactions, where Met is particularly enriched (40,41). Contrary to the oxidation of surface-exposed Met in folded proteins, which may have little effect on protein function (42), Met oxidation in buried regions should dramatically affect folding and function of cellular proteins.…”

“…4). These properties could make these enzymes better equipped to interact with unfolded proteins, which expose hydrophobic residues usually confined to the core regions of folded proteins (40,41). Therefore, the high content of aromatic and aliphatic residues in MSRs could be an important factor promoting the ability of these enzymes to preferentially use unfolded protein substrates through hydrophobic or -stacking interactions.…”

Electrostatic Interactions in Protein Structure, Folding, Binding, and Condensation

“…The radial distributions are protein-size dependent. In Figure a, right panel, we display the results for six types of side chains, calculated here on 507 proteins with radii of gyration between 13 and 17 Å (taken from a larger nonredundant set of globular proteins with high-resolution structures). These results largely recapitulate those calculated previously on a smaller set of 85 proteins .…”

Role of Ordered Proteins in the Folding-Upon-Binding of Intrinsically Disordered Proteins

“…Because apo structures are rarely available, we approximated these structures by simply deleting the complementary protein from the disordered protein complex. As a basis for comparison, we also analyzed 775 pdb structures that were identified in a previously published list of globular, monomeric proteins . The residues from these globular, monomeric structures were similarly classified as either core (C G ) or surface (S G ).…”