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Open Access Highly Accessed Methodology article

Improved multi-level protein–protein interaction prediction with semantic-based regularization

Claudio Saccà1, Stefano Teso2, Michelangelo Diligenti1 and Andrea Passerini2*

Author Affiliations

1 Dipartimento di Ingegneria dell’Informazione e Scienze Matematiche, University of Siena, Siena, Italy

2 Dipartimento di Ingegneria e Scienza dell’Informazione, University of Trento, Trento, Italy

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BMC Bioinformatics 2014, 15:103  doi:10.1186/1471-2105-15-103

Published: 12 April 2014



Protein–protein interactions can be seen as a hierarchical process occurring at three related levels: proteins bind by means of specific domains, which in turn form interfaces through patches of residues. Detailed knowledge about which domains and residues are involved in a given interaction has extensive applications to biology, including better understanding of the binding process and more efficient drug/enzyme design. Alas, most current interaction prediction methods do not identify which parts of a protein actually instantiate an interaction. Furthermore, they also fail to leverage the hierarchical nature of the problem, ignoring otherwise useful information available at the lower levels; when they do, they do not generate predictions that are guaranteed to be consistent between levels.


Inspired by earlier ideas of Yip et al. (BMC Bioinformatics 10:241, 2009), in the present paper we view the problem as a multi-level learning task, with one task per level (proteins, domains and residues), and propose a machine learning method that collectively infers the binding state of all object pairs. Our method is based on Semantic Based Regularization (SBR), a flexible and theoretically sound machine learning framework that uses First Order Logic constraints to tie the learning tasks together. We introduce a set of biologically motivated rules that enforce consistent predictions between the hierarchy levels.


We study the empirical performance of our method using a standard validation procedure, and compare its performance against the only other existing multi-level prediction technique. We present results showing that our method substantially outperforms the competitor in several experimental settings, indicating that exploiting the hierarchical nature of the problem can lead to better predictions. In addition, our method is also guaranteed to produce interactions that are consistent with respect to the protein–domain–residue hierarchy.