From Protein Structure to Function with Bioinformatics.pdf

Chapter 3Comparative Protein Structure ModellingAndrás FiserAbstract A prerequisite to understand cell functioning on the system level is theknowledge of three-dimensional protein structures that mediate biochemical interactions.The explosion in the number of available gene sequences set the stage forthe next step in genome scale projects, to obtain three dimensional structures foreach protein. To achieve this ambitious goal, the costly and slow structure determinationexperiments are boosted with theoretical approaches. The current state andrecent advances in structure modelling approaches are reviewed here, with specialemphasis on comparative structure modelling techniques.3.1 Introduction3.1.1 Structure Determines FunctionFunctional characterization of proteins is one of the most frequent problems in biology.While sequences provide valuable information, their high plasticity makes it frequentlyimpossible to identify functionally relevant residues (Todd et al. 2002). For example incase of enzymes, a similar function can be assumed between two proteins if theirsequence identity is above 40%, but if the sequence identity drops in between 30–40%only the first three Enzyme Commission (EC) numbers can be predicted reliably, andonly at 90% accuracy level. Below 30% sequence identity, structural information is necessaryto essential for functional annotation. Meanwhile it is estimated that 75% ofhomologous enzymes share less than 30% identical positions (Todd et al. 2001). Anotherquantitative study on sequence and function divergence was based on the Gene Ontologyclassification of function in 6,828 protein families (Sangar et al. 2007). It was confirmedthat among homologous proteins, the proportion of divergent functions decreases dramaticallyif a threshold of sequence identity is 50% or higher. However, even for proteinsA. FiserDepartment of Biochemistry, Albert Einstein College of Medicine, 1300 MorrisPark Ave, Bronx 10461, NY, USAe-mail: andras@fiserlab.org, http://www.fiserlab.orgD.J. Rigden (ed.) From Protein Structure to Function with Bioinformatics, 57© Springer Science + Business Media B.V. 2009