Author SummaryThe sequencing of genomes from different species has provided a unique opportunity for comparative analysis and opened the door to a higher level of understanding of living organisms. However, identifying the biochemical functions of the protein products coded by these genes has proved to be a major challenge. Computational methods that have been used to assign functions to such sequences often result in high levels of misannotations. Nature's strategy of evolving new function provides clues for formulating an accurate predictive scheme for functional annotation. Constraints associated with substrate binding properties and chemistry have been shown to be major determinants of guiding the evolution of new function. In this study, the authors have explored the functional and structural constraints imposed by complex cofactors on the evolution of new functions. Analysis of the large "two dinucleotide binding domains" flavoproteins (tDBDF) superfamily using structural comparisons and other bioinformatics approaches shows how structural requirements associated with cofactor reactivity constrain the mode of protein–protein interactions while providing the major route for evolution of functional diversification. The evolutionary framework established in this work may be generally useful for the analysis of functional divergence in other enzyme superfamilies that use complex cofactors.
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