AlphaFold2: A Role for Disordered Protein/Region Prediction?

Carter J Wilson; Wing-Yiu Choy; Mikko Karttunen

doi:10.3390/ijms23094591

AlphaFold2: A Role for Disordered Protein/Region Prediction?

Int J Mol Sci. 2022 Apr 21;23(9):4591. doi: 10.3390/ijms23094591.

Authors

Carter J Wilson^{1

2}, Wing-Yiu Choy³, Mikko Karttunen^{2

4

5}

Affiliations

¹ Department of Mathematics, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B7, Canada.
² Centre for Advanced Materials and Biomaterials Research, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B7, Canada.
³ Department of Biochemistry, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5C1, Canada.
⁴ Department of Physics and Astronomy, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B7, Canada.
⁵ Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 3K7, Canada.

Abstract

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 naïve, 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).

Keywords: AlphaFold2; IDPs/IDRs; biophysics; disordered proteins; machine-learning; molecular dynamics; simulation; structural bioinformatics.

MeSH terms

Intrinsically Disordered Proteins* / chemistry
Molecular Dynamics Simulation
Protein Conformation
Protein Domains
Protein Structure, Secondary

Substances

Intrinsically Disordered Proteins