Multi-scale sequence correlations increase proteome structural disorder and promiscuity

TL;DR

This study reveals that multi-scale sequence correlations in proteins are linked to structural disorder and promiscuity, providing insights into protein interactions and aggregation diseases.

Contribution

It introduces a novel analytical theory connecting sequence correlations with protein disorder and promiscuity, supported by statistical analysis.

Findings

Sequence correlations are enhanced in disordered proteins and hubs.

Disordered proteins have higher sequence order than ordered ones.

The theory predicts robustness across amino acid compositions.

Abstract

Numerous experiments demonstrate a high level of promiscuity and structural disorder in organismal proteomes. Here we ask the question what makes a protein promiscuous, i.e., prone to non-specific interactions, and structurally disordered. We predict that multi-scale correlations of amino acid positions within protein sequences statistically enhance the propensity for promiscuous intra- and inter-protein binding. We show that sequence correlations between amino acids of the same type are statistically enhanced in structurally disordered proteins and in hubs of organismal proteomes. We also show that structurally disordered proteins possess a significantly higher degree of sequence order than structurally ordered proteins. We develop an analytical theory for this effect and predict the robustness of our conclusions with respect to the amino acid composition and the form of the microscopic potential between the interacting sequences. Our findings have implications for understanding molecular mechanisms of protein aggregation diseases induced by the extension of sequence repeats.