Bioinformatical Approaches to Unstructured/Disordered Proteins and Their Interactions

Abstract

Abstract. Intrinsically unstructured/disordered proteins (IUPs/IDPs) exist as highly flexible conformational ensembles without adopting a stable three-dimensional structure. Experimental and bioinformatical studies in the past two decades have shown that these proteins play a central role in various signaling and regulatory processes. Accordingly, their frequency in higher eukaryotes reaches high proportions and their malfunction can be connected to a wide variety of diseases. Recognizing the biological importance of these proteins motivated researchers to understand various aspects of disordered proteins and protein segments from the viewpoint of biochemistry, molecular biology and pharmacology. In general, IDPs are difficult to study experimentally because of the lack of a unique structure in the isolated form. Nevertheless, various bioinformatics tools developed over the last few years enable their identification and characterization using only the amino acid sequence. In this chapter -after a brief introduction to IDPs in generalwe present a small survey of current methods aimed at identifying disordered proteins or protein segments, focusing on those that are publicly available as web servers. We also discuss in more detail approaches that predict disordered regions and specific regions involved in protein binding by modeling the physical background of protein disorder. Furthermore, we argue that the heterogeneity of disordered segments needs to be taken into account for a better understanding of protein disorder and the correct use and interpretation of the output of disorder prediction algorithms.

CABS-flex predictions of protein flexibility compared with NMR ensembles

“…Most disorder prediction algorithms (such as disopred, Ward et al (2004)) perform well for stable, globular domains, or highly flexible disordered regions without a strong structural preference. However, their performance does not meet expectations for structurally ambiguous regions (Mészáros et al, 2014). Therefore, in comparison to sequence-based disorder prediction algorithms, cabs-flex is better suited to detecting non-obvious dynamic behavior (e.g.…”

“…The CABS-flex method provides an alternative to other efficient computational tools generating protein residue fluctuation profiles, such as sequence-based predictors of protein disordered regions (Mészáros et al , 2014) or coarse-grained normal mode analysis (NMA; Ma, 2005). Most disorder prediction algorithms [such as DISOPRED, Ward et al (2004)] perform well for stable globular domains or highly flexible disordered regions without a strong structural preference.…”

Software tools for simultaneous data visualization and T cell epitopes and disorder prediction in proteins

“…The high-confidence predictions of ANCHOR covering these binding regions in the Nterminal domain, Fig. 5C, is the strongest prediction-level evidence for the presence of disordered binding regions (as opposed to coiled-coil region or a short collapsed structure) [40].…”

“…The principles of the combined usage of different methods in the field of protein structure/function analysis are described by various authors, frequently using the example of human p53, which is one of the most complex IDPs. Comparing several disorder predictors, optimized for various typical lengths of disorder, and disordered binding region -prediction by ANCHOR, Meszaros and colleagues gave a profile of p53 disordered binding regions encompassing short linear binding motifs [40]. Huart and Hupp have shown that p53 long disordered regions were enriched in potential disorder-based binding motifs which overlap numerous sites of post-translational modifications, and suggested how amino acid modifications evolved to regulate dynamically the p53 interactome [18].…”

Is Five Percent Too Small? Analysis of the Overlaps between Disorder, Coiled Coil and Collagen Predictions in Complete Proteomes

“…Thus, the exact identification of IDPs and intrinsically disordered segments is an important aspect in large-scale structure-function studies. It has recently been pointed out that some structural elements, referred to as oligomeric fibrillar motifs below, are often predicted to be disordered by current IDP prediction algorithms [ 3 , 4 ]. Although the occurrence of structured motifs within low-complexity segments and other regions regularly predicted as IDPs has been noted [ 5 ], these are rarely taken explicitly into account when evaluating IDP abundance at the proteome level.…”