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Multi-level machine learning prediction of protein-protein interactions

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Julian Zubek, Marcin Tatjewski, Adam Boniecki, Maciej Mnich, Subhadip Basu, Dariusz Plewczynski


Accurate identification of protein-protein interactions (PPI) is the key step in understanding proteins' biological functions, which are typically context-dependent. Many existing PPI predictors rely on aggregated features from protein sequences, however only a few methods exploit local information about specific residue contacts.

In this work we present a two-stage machine learning approach for prediction of protein-protein interactions. We start with the carefully filtered data on protein complexes available for Saccharomyces cerevisiae, Escherischia coli and Homo sapiens in the Protein Data Bank (PDB) database. First, we build linear descriptions of interacting and non-interacting sequence segment pairs based on their inter-residue distances. Secondly, we train machine learning / to predict binary segment interactions for any two short sequence fragments. The final prediction of the protein-protein interaction is done using the 2D matrix representation of all-against-all possible interacting sequence segments of both analysed proteins. The level-I predictor achieves 0.88 AUC for micro-scale, i.e. residue-level prediction. The level-II predictor improves the results further by more complex learning paradigm. We perform 30-fold macro-scale, i.e. protein-level cross-validation experiment. The level-II predictor using PSIPRED-predicted secondary structure reaches 0.70 precision, 0.68 recall, and 0.70 AUC, whereas other popular methods provide results below 0.6 threshold (recall, precision, AUC). Our results demonstrate that multi-scale sequence features aggregation procedure is able to improve the machine learning results by more than 10% as compared to other sequence representations.


The repository contains full source code of the experimental pipeline. For the trained classifiers and the training and testing data check experiments/yeast_experiment_psipred directory.