title: Space constrained homology modelling: the paradigm of the RNA-dependent RNA polymerase of dengue (type II) virus.
abstract: Protein structure is more conserved than sequence in nature. In this direction we developed a novel methodology that significantly improves conventional homology modelling when sequence identity is low, by taking into consideration 3D structural features of the template, such as size and shape. Herein, our new homology modelling approach was applied to the homology modelling of the RNA-dependent RNA polymerase (RdRp) of dengue (type II) virus. The RdRp of dengue was chosen due to the low sequence similarity shared between the dengue virus polymerase and the available templates, while purposely avoiding to use the actual X-ray structure that is available for the dengue RdRp. The novel approach takes advantage of 3D space corresponding to protein shape and size by creating a 3D scaffold of the template structure. The dengue polymerase model built by the novel approach exhibited all features of RNA-dependent RNA polymerases and was almost identical to the X-ray structure of the dengue RdRp, as opposed to the model built by conventional homology modelling. Therefore, we propose that the space-aided homology modelling approach can be of a more general use to homology modelling of enzymes sharing low sequence similarity with the template structures.
authors.affiliation: Bioinformatics & Medical Informatics Team, Biomedical Research Foundation, Academy of Athens, Soranou Efessiou 4, 11527 Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Vlachakis
authors.forename: Dimitrios Georgios
authors.initials: DG
authors.lastname: Kontopoulos
authors.forename: Sophia
authors.initials: S
authors.lastname: Kossida
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003716:Dengue Virus / Q000145:classification / Q000201:enzymology* / Q000235:genetics; D001908:Diarrhea Viruses, Bovine Viral / Q000201:enzymology / Q000235:genetics; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment / Q000706:statistics & numerical data; D055672:Static Electricity
chemical_list: D012324:RNA-Dependent RNA Polymerase