Hybrid sequence-structure based HMM models leverage theidentification of homologous proteins: the example of class II fusion

We present a sequence-structure based method characterizing a set of functionally related proteins exhibiting low sequence identity and loose structural conservation. Given a (small) set of structures, our method consists of three main steps. First, pairwise structural alignments are combined with multi-scale geometric analysis to produce structural motifs i.e. regions structurally more conserved than the whole structures. Second, the sub-sequences of the motifs are used to build profile hidden Markov models (HMM) biased towards the structurally conserved regions. Third, these HMM are used to retrieve from UniProtKB proteins harboring signatures compatible with the function studied, in a bootstrap fashion.\n\nWe apply these hybrid HMM to investigate two questions related to class II fusion proteins, an especially challenging class since known structures exhibit low sequence identity (less than 15%) and loose structural similarity (of the order of 15[A] in lRMSD). In a first step, we compare the performances of our hybrid HMM against those of sequence based HMM. Using various learning sets, we show that both classes of HMM retrieve unique species. The number of unique species reported by both classes of methods are comparable, stressing the novelty brought by our hybrid models. In a second step, we use our models to identify 17 plausible HAP2-GSC1 candidate sequences in 10 different drosophila melanogaster species. These models are not identified by the PF[A]M family HAP2-GCS1 (PF10699), stressing the ability of our structural motifs to capture signals more subtle than whole Pfam domains.\n\nIn a more general setting, our method should be of interest for all cases functional families with low sequence identity and loose structural conservation.\n\nOur software tools are available from the FunChaT package of the Structural Bioinformatics Library (http://sbl.inria.fr).