From Protein Structure to Function with Bioinformatics.pdf

68 A. Fiserinto conserved core regions, variable loops that connect them, and side chains thatdecorate the backbone (Topham et al. 1993). A widely used program in this classis COMPOSER (Sutcliffe et al. 1987). The accuracy of a model can be somewhatincreased when more than one template structure is used to construct the frameworkand when the templates are averaged into the framework using weights correspondingto their sequence similarities to the target sequence (Srinivasan andBlundell 1993).Modelling by Segment Matching or Coordinate ReconstructionThe basis of modelling by coordinate reconstruction is the finding that most hexapeptidesegments of protein structure can be clustered into only 100 structurallydifferent classes (Unger et al. 1989). Thus, comparative models can be constructedby using a subset of atomic positions from template structures as “guiding” positions,and by identifying and assembling short, all-atom segments that fit theseguiding positions. The guiding positions usually correspond to the Cα atoms of thesegments that are conserved in the alignment between the template structure andthe target sequence. The all-atom segments that fit the guiding positions can beobtained either by scanning all the known protein structures, including those thatare not related to the sequence being modelled (Claessens et al. 1989; Holm andSander 1991), or by a conformational search restrained by an energy function(Bruccoleri and Karplus 1990; van Gelder et al. 1994). For example, a generalmethod for modelling by segment matching (SEGMOD) (Levitt 1992) is guided bythe positions of some atoms (usually Cα atoms) to find the matching segments in arepresentative database of all known protein structures. This method can constructboth main chain and side chain atoms, and can also model gaps. Even some sidechain modelling methods (Chinea et al. 1995) and the class of loop constructionmethods based on finding suitable fragments in the database of known structures(T. A. Jones and Thirup 1986) can be seen as segment matching or coordinatereconstruction methods.Modelling by Satisfaction of Spatial RestraintsThe methods in this class begin by generating many constraints or restraints on thestructure of the target sequence, using its alignment to related protein structures asa guide. The procedure is conceptually similar to that used in determination of proteinstructures from NMR-derived restraints. The restraints are generally obtainedby assuming that the corresponding distances between aligned residues in the templateand the target structures are similar. These homology-derived restraints areusually supplemented by stereochemical restraints on bond lengths, bond angles,dihedral angles, and non-bonded atom-atom contacts that are obtained from amolecular mechanics force field (Brooks et al. 1983). The model is then derived byminimizing the violations of all the restraints. This can be achieved either by distancegeometry or real-space optimization. For example, an elegant distance geom-