Online homology modeling as a means of bridging the sequence-structure gap

For even the best-studied species, there is a large gap in their representation in the protein databank (PDB) compared to within sequence databases. Typically, less than 2% of sequences are represented in the PDB. This is partly due to the considerable experimental challenge and manual inputs required to solve three dimensional structures by methods such as X-ray diffraction and multi-dimensional nuclear magnetic resonance (NMR) spectroscopy in comparison to high-throughput sequencing. This gap is made even wider by the high level of redundancy within the PDB and under-representation of some protein categories such as membrane-associated proteins which comprise approximately 25% of proteins encoded in genomes. A traditional route to closing the sequence-structure gap is offered by homology modeling whereby the sequence of a target protein is modeled on a template represented in the PDB using in silico energy minimization approaches. More recently, online homology servers have become available that automatically generate models from proffered sequences. However, many online servers give little indication of the structural plausibility of the generated model. In this paper, the online homology server Geno3D will be described. This server uses similar software to that used in modeling structures during structure determination and thus generates data allowing determination of the structural plausibility of models. For illustration, modeling of a chemotaxis protein (CheY) from Pseudomononas entomophila L48 (accession YP_609298) on a template (PDB id. 1mvo), the phosphorylation domain of an outer membrane protein PhoP from Bacillus subtilis, will be described.