Overall Protein Model Construction Methods

Two philosophically different methods are commonly used to construct the target molecule s 3-D structure. One method is to use the best model, and the other is to use a consensus model. In the best model method, a series of intermediate protein models are constructed and the best one is selected to be the starting point for refinement (as the name implies). The consensus model uses intermediate structures to construct an average model, and that average model is used as the starting point for the refinement of the structure (as will be discussed in the NMRClust section). The number of intermediate protein models and the extent of energy minimization for the final protein model is user definable. 

The three protein model constructing methodologies discussed in this section use different conceptual means to construct a protein model. The refinement methodologies inherent to these methods were not discussed. In the section. Step 5 Refinement of Protein Models, the refinement of the raw output of these methods (the protein model) to further reduce steric clashes is described. 

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In addition to conventional sequence motifs (Prosite, BLOCKS, PRINTS, etc.), the compilation of structural motifs indicative of specific functions from known structures has been proposed [268]. This should improve even the results obtained with multiple (one-dimensional sequence) patterns exploited in the BLOCKS and PRINTS databases. Recently, the use of models to define approximate structural motifs (sometimes called fuzzy functional forms, FFFs [269]) has been put forward to construct a library of such motifs enhancing the range of applicability of motif searches at the price of reduced sensitivity and specificity. Such approaches are supported by the fact that, often, active sites of proteins necessary for specific functions are much more conserved than the overall protein structure (e.g. bacterial and eukaryotic serine proteases), such that an inexact model could have a partly accurately conserved part responsible for function. As the structural genomics projects produce a more and more comprehensive picture of the structure space with representatives for all major protein folds and with the improved homology search methods linking the related sequences and structures to such representatives, comprehensive libraries of highly discriminative structural motifs are envisionable. 

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