Evolutionary trace for prediction and redesign of protein functional sites

Abstract

The evolutionary trace (ET) is the single most validated approach to identify protein functional determinants and to target mutational analysis, protein engineering and drug design to the most relevant sites of a protein. It applies to the entire proteome; its predictions come with a reliability score; and its results typically reach significance in most protein families with 20 or more sequence homologs. In order to identify functional hot spots, ET scans a multiple sequence alignment for residue variations that correlate with major evolutionary divergences. In case studies this enables the selective separation, recoding, or mimicry of functional sites and, on a large scale, this enables specific function predictions based on motifs built from select ET-identified residues. ET is therefore an accurate, scalable and efficient method to identify the molecular determinants of protein function and to direct their rational perturbation for therapeutic purposes. Public ET servers are located at: http://mammoth.bcm.tmc.edu/.

Fig. 1

The Evolutionary Trace method. The proteins making up the multiple sequence alignment are divided into groups based on the phylogenic tree. Each group has a representative sequence with the invariant residues. The ET method extracts the relative evolutionary importance of the residues in example where the top ranked residues are marked 1, 2 and 3. These residues are then mapped onto the protein structure in order to visualize functional site.