From Protein Structure to Function with Bioinformatics.pdf

64 A. Fiserbetween fold recognition and comparative modelling: while both are templatebased and deliver a 3D description of the target as a result, fold recognition aims atidentifying the general 3D shape of the target sequence or at least the class ofshapes where it belongs to, while comparative modelling aims at generating an allatom model for the entire target sequence.3.2.2 Selecting TemplatesOnce a list of potential templates is obtained using searching methods, it is necessaryto select one or more templates that are appropriate for the particular modellingproblem. Several factors need to be taken into account when selecting a template.3.2.2.1 Considerations in Template SelectionThe simplest template selection rule is to select the structure with the highestsequence similarity to the modelled sequence. The family of proteins that includesthe target and the templates can frequently be organized into sub-families. Theconstruction of a multiple alignment and a phylogenetic tree (Felsenstein 1981) canhelp in selecting the template from the subfamily that is closest to the targetsequence. The similarity between the “environment” of the template and the environmentin which the target needs to be modelled should also be considered. Theterm “environment” is used here in a broad sense, including everything that is notthe protein itself (e.g., solvent, pH, ligands, quaternary interactions). If possible, atemplate bound to the same or similar ligands as the modelled sequence shouldgenerally be used. The quality of the experimentally determined structure is anotherimportant factor in template selection. Resolution and R-factor of a crystal structureand the number of restraints per residue for an NMR structure are indicative of theiraccuracy. For instance, if two templates have comparable sequence similarity to thetarget, the one determined at the highest resolution should generally be used. Thecriteria for selecting templates also depend on the purpose of a comparative model.For example, if a protein-ligand model is to be constructed, the choice of the templatethat contains a similar ligand is probably more important than the resolutionof the template.3.2.2.2 Advantage of Using Multiple TemplatesIt is not necessary to select only one template. In fact, the optimal use of several templatesincreases the model accuracy (Fernandez-Fuentes et al. 2007a, b; Sanchez andSali 1997; Venclovas and Margelevicius 2005); however, not all modelling programsare designed to accept more than one template. The benefit of combining multipletemplate structures can be twofold. First, multiple template structures may be alignedwith different domains of the target, with little overlap between them, in which case,