From Protein Structure to Function with Bioinformatics.pdf

7 Predicting Protein Function from Surface Properties 17790% of the actual binding sites tested were represented among the top three rankedpockets (see Fig. 7.4).7.4.2.3 Theoretical Microscopic Titration CurvesThe electrostatic properties of a protein surface influence the behaviour of ionisablegroups in the neighbourhood. In many cases, the ionisable side chains intimatelyinvolved in chemical catalysis have neighbourhoods that significantlyperturb their ionisation. In particular, they are often found to be able to maintaina particular partially protonated state over an abnormally large pH range. Theresult is pKa values and titration curves that differ in value and shape, respectively,compared to those of average residues of the same type. Since electrostaticproperties and ionization behaviour can be calculated computationally, this providesthe opportunity to predict catalytic site residues based on their anomaloustheoretical microscopic titration curves (e.g. Antosiewicz et al. 1994; Elcock,2001). An application of this method, with THEMATICS (standing for theoreticalmicroscopic titration curves), successfully flagged catalytic residues in sevendifferent enzymes structures, with rather few false positives, and made no predictionsfor a non-catalytic protein included as a control (Ondrechen et al. 2001).The method has since been improved by the development of statistical measuresfor categorising theoretical titration curves (Ko et al. 2005), and the introductionFig. 7.4 Q-SiteFinder prediction. The active site molecular surface of acetylcholinesterase (PDBcode: 1EVE) where the binding location of the small molecule drug, aricept, is well defined bythe top ranked pocket (transparent grey surface)