Canonical methods of protein evolution include diversification of folds through genetic and epigenetic alterations including point mutations, silencing, deletions and duplication. Following a survey of the entire human mutation database, we describe a new mechanism ‘structural capacitance’ that may enable the de novo generation over rapid timescales of new protein microstructures in previously disordered regions.

Analysing on 27,369 disease mutations and 39,920 polymorphisms, we define four order-disorder transitions (including D->O, O->D, D->D and O->O) based on disordered regions prediction with help of VSL2B. Overall analysis on physical-chemical properties, 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. Functional analysis of these mutations reveals that relatively high percentage of D->O disease mutations are modified residues, active sites and metal binding sites. None of D->O mutations including both pathogenic and nonsense mutations can be found in coiled-coil or transmembrane regions. Ordered regions in wild type seem to have more chemical group binding sites and disulphide bonds. What is more, predicted long disordered region (containing D->O mutations) have been extracted and mapped to post-translational site and Pfam domain annotations. Results showed that majority of these long predicted disordered regions overlap with Pfam domains and are enriched with post-translational modification sites including phosphorylation and glycosylation.

These new elements of protein microstructure generated by D->O transitions are functionally implicated in the pathogenesis of a wide range of human diseases. The finding has implications for the ancestral diversification of protein folds, the engineering of highly evolvable proteins, and the identification and selective targeting of human disease epitopes.