Abstract
BackgroundThe functional sites of a protein present important information for determining its cellular function and are fundamental in drug design. Accordingly, accurate methods for the prediction of functional sites are of immense value. Most available methods are based on a set of homologous sequences and structural or evolutionary information, and assume that functional sites are more conserved than the average. In the analysis presented here, we have investigated the conservation of location and type of amino acids at functional sites, and compared the behaviour of functional sites between different protein domains.ResultsFunctional sites were extracted from experimentally determined structural complexes from the Protein Data Bank harbouring a conserved protein domain from the SMART database. In general, functional (i.e. interacting) sites whose location is more highly conserved are also more conserved in their type of amino acid. However, even highly conserved functional sites can present a wide spectrum of amino acids. The degree of conservation strongly depends on the function of the protein domain and ranges from highly conserved in location and amino acid to very variable. Differentiation by binding partner shows that ion binding sites tend to be more conserved than functional sites binding peptides or nucleotides.ConclusionThe results gained by this analysis will help improve the accuracy of functional site prediction and facilitate the characterization of unknown protein sequences.
Highlights
The functional sites of a protein present important information for determining its cellular function and are fundamental in drug design
Sequence alignments of protein domains were retrieved from the SMART database and used to scan the protein sequences of the protein data bank (PDB) with domain-specific Hidden Markov Models (HMMs)
Wherever a domain was identified, all interactions between an amino acid belonging to this domain and any ligand were extracted and the position of the interacting amino acid was transferred onto the HMM consensus
Summary
The functional sites of a protein present important information for determining its cellular function and are fundamental in drug design. Most available methods are based on a set of homologous sequences and structural or evolutionary information, and assume that functional sites are more conserved than the average. BMC Bioinformatics 2005, 6:210 http://www.biomedcentral.com/1471-2105/6/210 structural approaches that search for ligand binding pockets on the protein surface using molecular modelling [4,5], network analysis [6], or compare the protein surface to structures with known interacting sites [7,8], many methods are based on a set of homologous sequences combined with evolutionary or structural information. Beginning with a sequence identity tree from a set of homologous proteins, the tree is scanned for subgroupspecific residues, which are invariant within the subgroup but vary between subgroups These residues, called evolutionary trace residues, and the residues that are invariant in all sequences are mapped onto a representative 3D structure and clusters of high ranking residues, corresponding to the inner nodes of the tree, are searched. A similar approach is focusing more on structural information and calculates a conservation score at each position under consideration of the behaviour of spatial neighbours [14]
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