From Protein Structure to Function with Bioinformatics.pdf

80 A. Fiser(Clore et al. 1993). Changes in the environment (e.g., oligomeric state, crystal packing,solvent, ligands) can also have a significant effect on the structure (Faber andMatthews 1990). Overall, comparative modelling based on templates with more than40% identity is almost as good as medium resolution experimental structures, simplybecause the proteins at this level of similarity are likely to be as similar to each otheras are the structures for the same protein determined by different experimental techniquesunder different conditions. However, the caveat in comparative protein modellingis that some regions, mainly loops and side chains, may have larger errors.The performance of comparative modelling may sometimes appear overstated,because what is usually discussed in the literature are the mean values of backbonedeviations. However, individual errors in certain residues essential for the proteinfunction, even in the context of an overall backbone RMSD of less than 1 Å, canstill be large enough to prevent reliable conclusions to be drawn regarding mechanism,protein function or drug design.3.4 Applications of Comparative Modelling3.4.1 Modelling of Individual ProteinsComparative modelling is often an efficient way to obtain useful information aboutthe proteins of interest. For example, comparative models can be helpful in designinggenetic experiments, such as designing mutants to test hypotheses about the functionof a protein (Vernal et al. 2002; G. Wu et al. 1999), identifying active and bindingsites (Sheng et al. 1996). Models are useful for studying protein-protein and proteinligandinteractions, designing inhibitors, e.g. searching, designing and improving ligandsfor a given binding site (Ring et al. 1993), modelling substrate specificity (L. Z.Xu et al. 1996), predicting antigenic epitopes (Sali et al. 1993), simulating proteinproteindocking (Vakser 1995). Models can reveal physico-chemical features that arenot possible to guess from sequence information only, for instance, inferring functionfrom calculated electrostatic potential around the protein (Sali et al. 1993) and ingeneral, rationalizing known experimental observations (Fiser et al. 2003). Modelsare also very useful to enhance structure solutions by facilitating molecular replacementin X-ray structure determination (Schwarzenbacher et al. 2008), refining modelsbased on NMR constraints (Barrientos et al. 2001), confirming a remote structuralrelationship (Guenther et al. 1997; G. Wu et al. 1999).3.4.2 Comparative Modelling and the Protein Structure InitiativeThe full impact of the genome projects will only be realized once we assign andunderstand the functions of the new encoded proteins. This understanding will be