From Protein Structure to Function with Bioinformatics.pdf

174 N.J. Burgoyne and R.M. Jackson7.3.4 Combining Surface Properties for Function PredictionProtein surface properties other than electrostatics and hydrophobicity, can alsoinfluence protein function. For example, several other properties have beenincluded in the surface-based function prediction procedure of HotPatch (Pettitet al. 2007). Here function can be assigned by comparison to databases of proteinswith similar functions. Eleven properties (including four different electrostaticproperties, three measures of concavity and roughness, and four measuresof hydrophobicity and hydrophilicity), are used to describe fifteen different,hierarchically arranged, protein surface properties. These defined functionsinclude the generic function (the surface patch has a property) that breaks into abinding function (comprising protein-protein, oligomeric, DNA-RNA, smallmoleculeand carbohydrate interfaces), an enzyme function (including protease,hydrolase, transferase, oxidoreductase and kinase) and small ion binding (anionsand cations) functions. Relationships between the properties of each of the functionalgroups are defined and patches from a query protein can be assigned basedon similarity. Patches that match none of the categories can be assigned as havingno known function.7.4 Protein-Ligand InteractionsPerhaps the most important functions directly relating to the surface of a protein arethe interactions made with other molecules. These are fundamental to all aspects oflife from metabolism to signalling and beyond. This section focuses on proteinsmallmolecule ligand interactions. Other forms of interaction are discussed laterand in Chapter 9. Small molecule ligands are important, not only as biologicalmolecules, but also as drug molecules which are used to control the aberrant functionof proteins in disease states.7.4.1 Properties of Protein-Ligand InteractionsProtein-ligand interfaces constitute two major groups; enzyme active site regionsthat bind small molecules for the purpose of performing chemical transformation,and binding pockets that bind without catalysis. Residues in the region of theactive site are under evolutionary pressure in order to conserve the catalytic activityas well as the ability to bind the required molecules specifically. Protein familiesthat transport or respond to small-molecules without catalysis obviously lack theevolutionary pressure to maintain catalytic activity and the properties of proteinligandbinding-sites often reflect the diversity in the small-molecules that arebound by different family members. The difficulties and costs associated with