LAUSR

Motivation Proteins often include multiple conserved domains. Various evolutionary events including duplication and loss of domains, domain shuffling, as well as sequence divergence contribute to generating complexities in protein structures, and consequently, in their functions. The evolutionary history of proteins is hence best modeled through networks that incorporate information both from the sequence divergence and the domain content. Here, a game‐theoretic approach proposed for protein network construction is adapted into the framework of multi‐objective optimization, and extended to incorporate clustering refinement procedure. Results The new method, MOCASSIN‐prot, was applied to cluster multi‐domain proteins from ten genomes. The performance of MOCASSIN‐prot was compared against two protein clustering methods, Markov clustering (TRIBE‐MCL) and spectral clustering (SCPS). We showed that compared to these two methods, MOCASSIN‐prot, which uses both domain composition and quantitative sequence similarity information, generates fewer false positives. It achieves more functionally coherent protein clusters and better differentiates protein families. Availability and implementation MOCASSIN‐prot, implemented in Perl and Matlab, is freely available at http://bioinfolab.unl.edu/emlab/MOCASSINprot. Supplementary information Supplementary data are available at Bioinformatics online.