Optimizing Long Intrinsic Disorder Predictors With Protein Evolutionary Information

Abstract

Protein existing as an ensemble of structures, called intrinsically disordered, has been shown to be res ponsible for a wide variety of biological functions and to be common in nature. Here we focus on improving sequence-based predictions of long (> 30 amino acid residues) regions lacking specific 3-D structure by means of four new neural -network-based Predictors Of Natural Disordered Regions (PONDRs): VL3, VL3H, VL3P, and VL3E. PONDR VL3 used several features from a previously introduced PONDR VL2, but benefitted from optimized predictor models and a slightly larger (152 versus 145) set of disordered proteins that were cleaned of mislabeling errors found in the smaller set. PONDR VL3H utilized homologues of the disordered proteins in the training stage, while PONDR VL3P used attributes derived from sequence profiles obtained by PSI-BLAST searches. The measure of accuracy was the average between accuracies on disordered and ordered protein regions. By this measure, the 30-fold cross-validation accuracies of VL3, VL3H, and VL3P were, respectively, 83.6±1.4%, 85.3±1.4%, and 85.2±1.5%. By combining VL3H and VL3P, t he resulting PONDR VL3E achieved an accuracy of 86.7±1.4%. This is a significant improvement over our previous PONDRs VLXT (71.6±1.3%) and VL2 (80.9±1.4% ). The new disorder predictors with the corresponding datasets are freely accessible through the web server at www.ist.temple.edu/disprot.

Ligand specificity and evolution of liver X receptors

“…In contrast, an LXR ortholog from the chordate invertebrate Ciona intestinalis has different ligand specificity from the vertebrate LXRs, and this is exemplified by our computational analyses, suggesting that the endogenous ligands for the invertebrate LXRs may be a different, although possibly structurally related, group of molecules. Our novel use of calculated intrinsic disorder [22,36] suggests that following analysis of 21 sequences of LXRs across species, only Ciona LXR demonstrated a dramatic difference in LBD predicted disorder, a factor that could impact protein-protein and protein-ligand interactions. Our results also suggest that, like the estrogen receptors [43], LXRs may have an extensive evolutionary history in invertebrates.…”

“…Disorder prediction of protein sequences were performed using the PONDR VL3H algorithm [22] available at http://www.ist.temple.edu/disprot/predictor/php. The disorder calculations for each amino acid residue are available as Supplementary Table 2 and summarized in Supplementary Table 3.…”

“…An important factor in protein interactions with ligands or other proteins is presence of intrinsic structural disorder [22,36]. To assess whether disorder may account for pharmacological differences between the LXRs from different species, intrinsic disorder of the amino acid residues were predicted using the PONDR VL3H algorithm [22] and summarized by the percentage of residues with probability of disorder greater than 50% (Supplementary Table 2).…”

“…To assess whether disorder may account for pharmacological differences between the LXRs from different species, intrinsic disorder of the amino acid residues were predicted using the PONDR VL3H algorithm [22] and summarized by the percentage of residues with probability of disorder greater than 50% (Supplementary Table 2). Disorder probabilities were generally very similar across all LXRα and LXRβ sequences analyzed, whether analyzed by domain (DBD or LBD) or full-length protein sequence (Supplementary Table 3).…”

Functional Anthology of Intrinsic Disorder. 3. Ligands, Post-Translational Modifications, and Diseases Associated with Intrinsically Disordered Proteins

“…Long disordered regions in Swiss-Prot proteins were predicted using the VL3E predictor 19 . Each of the 196,326 Swiss-Prot proteins was labeled as putatively disordered if it contained a region with more than 40 consecutive amino acids predicted by VL3E to be intrinsically disordered; proteins predicted not to contain such long disordered regions were labeled as putatively ordered.…”