Disordered Regions (DRs) are defined as protein regions that lack a stable well-defined 3D structure. DRs are ubiquitous in proteins and highly related to human disease. In this work, we report a new mechanism termed ‘structural capacitance’, where gain-of-structural and functional changes at the individual protein level may be achieved through the introduction of point mutations into the germline that increase the hydrophobicity of key nucleating amino acids located in predicted regions of structural disorder. As a consequence, new microstructures are generated in previous disordered regions in the protein to obtain novel functions.

Using two widely used prediction tools of disordered regions (VSL2B and IUPred), we curate a large-scale up-to-date human disease mutation dataset that contains 12,307 proteins and 26,125 disease-associated mutations. We define the disorder state changes of regions with mutations according to into four categories: order-to-disorder (O→D), order-to-order (O→O), disorder-to-order (D→O) and disorder-to-disorder (D→D). We find that D→O transitions tend to increase the hydrophobicity after mutation, while O→D transitions have the opposite effect and for O→O and D→D transitions, the changes are not significant. For many of the D→O disease mutations found in long DR’s, we predict that the mutation does not increase the aggregation propensity of the protein, suggesting that the mutation exerts its affect not by loss of structure/folding but from gain of function.

While much emphasis on protein disorder focuses on lose-of-structure accompanied by lose-of-function, we propose a new paradigm of understanding human diseases through mutations that cause gain-of-structure/function via D→O transitions. These ‘structural capacitance residues’ (mutations in predicted disordered regions) could represent new epitopes worthy of further experimental investigation.  Our findings may have implications for the identification and selective targeting of human disease epitopes.