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bioRxiv · 10.1101/2023.05.25.542287

From interaction networks to interfaces: Scanning intrinsically disordered regions using AlphaFold2

Bret, H.·Andreani, J.·Guerois, R.
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Abstract

The revolution brought about by AlphaFold2 and the performance of AlphaFold2-Multimer open promising perspectives to unravel the complexity of protein-protein interaction networks. Nevertheless, the analysis of interaction networks obtained from proteomics experiments does not systematically provide the delimitations of the interaction regions. This is of particular concern in the case of interactions mediated by intrinsically disordered regions, in which the interaction site is generally small. Using a dataset of protein-peptide complexes involving intrinsically disordered protein regions that are non-redundant with the structures used in AlphaFold2 training, we show that when using the full sequences of the proteins involved in the interaction networks, AlphaFold2-Multimer only achieves 40% success rate in identifying the correct site and structure of the interface. By delineating the interaction region into fragments of decreasing size and combining different strategies for integrating evolutionary information, we managed to raise this success rate up to 90%. Beyond the correct identification of the interaction site, our study also explores specificity issues. We show the advantages and limitations of using the AlphaFold2 confidence score to discriminate between alternative binding partners, a task that can be particularly challenging in the case of small interaction motifs.

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Bret, H., Andreani, J., Guerois, R.. 2023-05-25. From interaction networks to interfaces: Scanning intrinsically disordered regions using AlphaFold2. https://doi.org/10.1101/2023.05.25.542287

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