Background: The current increase in Gene Ontology (GO) annotations of proteins in the existing genome databases and their use in different analyses have fostered the improvement of several biomedical and biological applications. To integrate this functional data into different analyses, several protein functional similarity measures based on GO term information content (IC) have been proposed and evaluated, especially in the context of annotation-based measures. In the case of topology-based measures, each approach was set with a specific functional similarity measure depending on its conception and applications for which it was designed. However, it is not clear whether a specific functional similarity measure associated with a given approach is the most appropriate, given a biological data set or an application, i.e., achieving the best performance compared to other functional similarity measures for the biological application under consideration.

Results: We show that, in general, a specific functional similarity measure often used with a given term IC or term semantic similarity approach is not always the best for different biological data and applications. We have conducted a performance evaluation of a number of different functional similarity measures using different types of biological data in order to infer the best functional similarity measure for each different term IC and semantic similarity approach. The comparisons of different protein functional similarity measures should help researchers choose the most appropriate measure for the biological application under consideration.

Availability: Human Protein-Protein interaction and co-expressed protein datasets used to assess the performance of different functional similarity measures are available here.

Any work dependent on open-source software owes debt to those who developed these tools. The authors thank everyone involved with free software, from the core developers to those who contributed to the documentation. Many thanks to the authors of the freely available libraries. This work has been supported by the National Research Foundation (NRF) in South Africa through Computational Biology (CBIO) group at University of Cape Town.