An automated stochastic approach to the identification of the protein specificity determinants and functional subfamilies

We present a method, SDPclust, for identification of protein functional subfamilies coupled with prediction of specificity-determining positions (SDPs). SDPclust predicts specificity in a phylogeny-independent stochastic manner, which allows for the correct identification of the specificity for proteins that are separated on a phylogenetic tree, but still bind the same ligand. SDPclust is implemented as a Web-server http://bioinf.fbb.msu.ru/SDPfoxWeb/ webcite and a stand-alone Java application available from the website.SDPclust performs a simultaneous identification of specificity determinants and specificity groups in a statistically robust and phylogeny-independent manner.The current explosion of data on protein sequences and structures lead to the emergence of techniques that go beyond standard annotation approaches, i.e. annotation by close homolog and homology-based family identification. These approaches usually start with a set of related sequences and perform a detailed analysis of each alignment position [1-15]. One of problems that such analysis can tackle is analysis of protein specificity. Let us assume that a protein family has undergone an ancient duplication that resulted in proteins that are related but perform different functions in the same organism. It is natural to assume that this functional divergence is mediated by mutation of certain amino acid positions. We call these positions specificity determinants, and this study is focused on their identification. We assume that specificity determinants, after mutation that allow for a new (sub-)function, should be under strong negative selection to let this newly asserted function to persist. This results is a very specific conservation pattern of the position in a multiple sequence alignment of the protein family: it is conserved among proteins that perform exactly same function and differ between different functional sub-groups. In this study, such positions are called SDPs (Specificity-Determining