Using a neural network and spatial clustering to predict the location of active sites in enzymes

Structural genomics projects aim to provide a sharp increase in the number of structures of functionally unannotated, and largely unstudied, proteins. Algorithms and tools capable of deriving information about the nature, and location, of functional sites within a structure are increasingly useful therefore. Here, a neural network is trained to identify the catalytic residues found in enzymes, based on an analysis of the structure and sequence. The neural network output, and spatial clustering of the highly scoring residues are then used to predict the location of the active site. A comparison of the performance of differently trained neural networks is presented that shows how information from sequence and structure come together to improve the prediction accuracy of the network. Spatial clustering of the network results provides a reliable way of finding likely active sites. In over 69% of the test cases the active site is correctly predicted, and a further 25% are partially correctly predicted. The failures are generally due to the poor quality of the automatically generated sequence alignments. We also present predictions identifying the active site, and potential functional residues in five recently solved enzyme structures, not used in developing the method. The method correctly identifies the putative active site in each case. In most cases the likely functional residues are identified correctly, as well as some potentially novel functional groups. (C) 2003 Elsevier Science Ltd. All rights reserved.