From Protein Structure to Function with Bioinformatics.pdf

3 Comparative Protein Structure Modelling 67input alignments. This selection is guided by a scoring function that determines thepreference of each alternatively aligned fragment of the target sequence in the structuralenvironment of the template. The scoring function has four terms, which areused to assess the compatibility of alternative variable segments in the protein environment:(a) environment specific substitution matrices from FUGUE (Shi et al.2001); (b) residue substitution matrix, BLOSUM (S. Henikoff and Henikoff 1992) (c)A 3D-1D substitution matrix, H3P2, that scores the matches of predicted secondarystructure of the target sequence to the observed secondary structures and accessibilitytypes of the template residues (Luthy et al. 1991); (d) a statistically derived residueresiduecontact energy term (Rykunov and Fiser 2007). MMM essentially performs alimited and inverse threading of short fragments: in this exercise the actual questionis not the identification of a right fold, but identification of the correct alignment mapping,among many alternatives, for sequence segments that are threaded on the samefold. These local mappings are evaluated in the context of the rest of the model, wherealignments provide a consistent solution and framework for the evaluation.3.2.4 Model BuildingWhen discussing the model building step within comparative protein structuremodelling it is useful to distinguish two parts: template dependent and templateindependent modelling. This distinction is necessary because certain parts of thetarget must be built without the aid of any template. These parts correspond to gaps inthe template sequence within the target-template alignment. Modelling of these regionsis commonly referred to as loop modelling problem. It is evident, that these loopsare responsible for the most characteristic differences between the template andtarget, and therefore are chiefly responsible for structural and consequentlyfunctional differences. In contrast to these loops, the rest of the target, and inparticular the conserved core of the fold of the target, is built using informationfrom the template structure. First, we will review a few major approaches of thislatter part, the template dependent modelling. This is also the logical first step duringthe building of a model, since the template dependent modelling step provides astructure for most of the target protein, which then serves as a starting structuralframework for any subsequent loop modelling exercise.3.2.4.1 Template Dependent ModellingModelling by Assembly of Rigid BodiesThe first and still widely used approach in comparative modelling is to assemblea model from a framework of small number of rigid bodies obtained from thealigned template protein structures (Blundell et al. 1987; Browne et al. 1969;Greer 1990). The approach is based on the natural dissection of the protein structure