From Protein Structure to Function with Bioinformatics.pdf

172 N.J. Burgoyne and R.M. Jacksonchoice of targets is often determined by the absence of detectable homology toproteins with known function with the aim that novel domains will be discovered.The main structure-based functional assignment methods involve the comparisonbetween local sequence and/or structural motifs. This topic is covered in detail inChapters 8 and 11. There are examples of allied approaches based on conservedareas of protein surface rather than protein structure in general. These examplesare covered below classified according to the surface properties described inSection 7.2.7.3.1 Hydrophobic SurfaceExtensive hydrophobic surface area is inherently unstable and is uncommon at theprotein-protein interface of non-obligate interactions, which must be independentlystable in water. Early protein interface prediction methods did involve the identificationof hydrophobic patches on the protein surface (Lijnzaad et al. 1996).However, these methods were usually applied to the prediction of obligate interfaces,such as protein oligomeric interactions. This problem is in some senses artificialbecause obligate interfaces are formed during protein folding, and theirprediction is inherently different to the prediction of non-obligate interfaces. Nonobligateinterfaces also have a slight increase in hydrophobic content, compared toprotein surface in general, and this presence is exploited as a guide in predicting thestructure of protein-protein complexes from the independent monomers (Berchanskiet al. 2004).7.3.2 Electrostatic SurfaceEnzyme active sites often employ regions of high electrostatic potential. Thisinvolves a trade off between biological function and stability (Beadle and Shoichet2002). Thus electrostatic potential may sometimes be utilised for the prediction offunctional sites. These regions on the surface can be used to predict active sites(Elcock 2001), and the location of DNA/RNA binding sites on proteins (Tsuchiyaet al. 2005). For example, PatchFinderPlus displays the largest positive electrostaticpatch on a protein (Fig. 7.2) that often corresponds to the binding site in nucleicacid binding proteins (Stawiski et al. 2003).There are examples where the conserved function is a consequence of a conservedsurface rather than a conserved protein fold or even conserved residues. Thebest known example of this is the catalytic triad of the serine-proteases, where eventhe three triad active site residues (most commonly His, Asp and Ser) can vary.What does stay the same is the surface of the active site and the electrostatic natureof the catalytic cavity. As a consequence there is value in comparing the molecularsurfaces of unknown proteins to databases of surfaces defined in a similar manner.