Combining predictors of natively unfolded proteins to detect a twilight zone between order and disorder in generic datasets

TL;DR

This paper introduces and evaluates new computational indexes for distinguishing natively unfolded proteins from folded ones, especially focusing on proteins in the ambiguous twilight zone, and proposes a consensus scoring method to improve classification accuracy.

Contribution

It presents a novel global index gVSL2, combines multiple indexes into a unanimous score SSU, and characterizes proteins in the ambiguous zone with intermediate properties.

Findings

gVSL2 and Poodle-W outperform other indexes across datasets

The SSU score effectively identifies proteins in the twilight zone

Unclassified proteins have intermediate structural and evolutionary properties

Abstract

Natively unfolded proteins lack a well defined three dimensional structure but have important biological functions, suggesting a re-assignment of the structure-function paradigm. Many proteins have amino acidic compositions compatible both with the folded and unfolded status, and belong to a twilight zone between order and disorder. This makes difficult a dichotomic classification of protein sequences into folded and natively unfolded ones. In this methodological paper dichotomic folding indexes are considered: hydrophobicity-charge, mean packing, mean pairwise energy, Poodle-W and a new global index, that is called here gVSL2, based on the local disorder predictor VSL2. The performance of these indexes is evaluated on different datasets. Poodle-W, gVSL2 and mean pairwise energy have good performance and stability in all the datasets considered and are combined into a strictly unanimous combination score SSU, that leaves proteins unclassified when the consensus of all combined indexes is not reached. The unclassified proteins: i) belong to an overlap region in the vector space of amino acidic compositions occupied by both folded and unfolded proteins; ii) are composed by approximately the same number of order-promoting and disorder-promoting amino acids; iii) have a mean flexibility intermediate between that of folded and that of unfolded proteins. These proteins reasonably have physical properties intermediate between those of folded and those of natively unfolded proteins and their structural properties and evolutionary history are worth to be investigated.