From Protein Structure to Function with Bioinformatics.pdf

302 I.A. Cymerman et al.performance of protein models, compared to experimental structures, in small moleculedocking. Two articles each show that protein models have value, but differ intheir comparisons with experimental structures. McGovern and Shoichet (2003)compared enrichment of known ligands vs decoys in docking results for holo, apoand model structures of nine enzymes. Templates used for model constructionshared 34–87% sequence identity with targets overall, and 45–100% identity in theregion of the binding site. In the best enrichment class were results for eight holostructure, two apo structures and three models, confirming the general superiorityof experimental structures. Nevertheless, modelled structures as a whole almostalways gave better than random selection of active compounds. There was a tendencyfor models built using more closely-related templates to perform better, butsmall conformational changes in the binding site could sometimes lead to poorperformance even in these cases. Later, Oshiro et al. (2004) compared the enrichmentof known active compounds in docking results for compound databases ofexperimental structures and comparative models, several for each, of CDK2 andfactor VIIa. The templates used for model construction shared 37–77% sequenceidentity in the vicinity of the binding site. Remarkably, where the local sequenceidentity of the model was higher than 50%, performance was similar to thatobtained with an experimental structure. Below 50% binding site identity, performancewas clearly degraded. Taken together, both papers encourage the use of modelsfor docking studies where the obviously preferable experimental structures areunavailable. It will be exciting to assess the performance of models in direct docking-for-functionpredictions such as those mentioned earlier.12.4 Practical ApplicationAfter the model is built, evaluated and perhaps deposited in the database, its role isto serve as a tool for the better understanding of protein structure-function relations.Typically, this analysis will be done by the bioinformatician or collaborators, butdatabases of models potentially allow any researcher to take explore what modelstructures say about function. Earlier chapters of this book show the many anddiverse ways in which structures may be used to infer function. Examples are nowpresented to illustrate the application of many of these techniques to structuralinformation generated by template-free modelling, fold recognition or comparativemodelling (Chapters 1–3, respectively).12.4.1 Plasticity of Catalytic Site ResiduesDespite the efforts undertaken by the structural genomics initiatives to cover theprotein fold space by providing structural templates for all existing protein families,there are cases where the sequence similarity criterion is insufficient to assign