Disorder Prediction Methods, Their Applicability to Different Protein Targets and Their Usefulness for Guiding Experimental Studies

Abstract

The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein's function. Disordered proteins have been found to play important roles in pivotal cellular functions, such as DNA binding and signalling cascades. Studying proteins with extended disordered regions is often problematic as they can be challenging to express, purify and crystallise. This means that interpretable experimental data on protein disorder is hard to generate. As a result, predictive computational tools have been developed with the aim of predicting the level and location of disorder within a protein. Currently, over 60 prediction servers exist, utilizing different methods for classifying disorder and different training sets. Here we review several good performing, publicly available prediction methods, comparing their application and discussing how disorder prediction servers can be used to aid the experimental solution of protein structure. The use of disorder prediction methods allows us to adopt a more targeted approach to experimental studies by accurately identifying the boundaries of ordered protein domains so that they may be investigated separately, thereby increasing the likelihood of their successful experimental solution.

Keywords: disorder prediction methods; intrinsic disorder; structural bioinformatics; types of disorder.

Figure 1

Number of publications relating to intrinsic disorder/unfolded proteins on PubMed since 1990. The early 2000’s saw a dramatic increase in research on these proteins. This figure has been updated from [1] using the same search terms within PubMed; intrinsically disordered, intrinsically unstructured, natively unfolded, intrinsically unfolded and intrinsically flexible.

Figure 2

IntFOLD server model of Cardiac MLP. The central and terminal regions are both thought to contain disorder, as found within the other members of the CRP family. The ordered domains are predicted to contain zinc binding sites; likely locations of zinc atoms are indicated by grey spheres. The image is rendered using PyMOL [56].