AlphaFold2: A Role for Disordered Protein/Region Prediction?

The development of AlphaFold2 marked a paradigm-shift in the structural biology community. Herein, we assess the ability of AlphaFold2 to predict disordered regions against traditional sequence-based disorder predictors. We find that AlphaFold2 performs well at discriminating disordered regions, but also note that the disorder predictor one constructs from an AlphaFold2 structure determines accuracy. In particular, a naive, but non-trivial assumption that residues assigned to helices, strands, and H-bond stabilized turns are likely ordered and all other residues are disordered results in a dramatic overestimation in disorder; conversely, the predicted local distance difference test (pLDDT) provides an excellent measure of residue-wise disorder. Furthermore, by employing molecular dynamics (MD) simulations, we note an interesting relationship between the pLDDT and secondary structure, that may explain our observations and suggests a broader application of the pLDDT for characterizing the local dynamics of intrinsically disordered proteins and regions (IDPs/IDRs).

Automated summary

The development of AlphaFold2 has brought a paradigm shift in structural biology and has shown excellent performance in predicting disordered regions. The accuracy of the constructed disorder predictor from AlphaFold2 structures varies, with the naive assumption of assigning residues to ordered or disordered based on helices, strands, and H-bond stabilized turns leading to a significant overestimation of disorder. The predicted local distance difference test (pLDDT) provides a reliable measure of residue-wise disorder and shows an interesting relationship with secondary structure.