title: Structure-based kernels for the prediction of catalytic residues and their involvement in human inherited disease.
abstract: BACKGROUND
  Enzyme catalysis is involved in numerous biological processes and the disruption of enzymatic activity has been implicated in human disease. Despite this, various aspects of catalytic reactions are not completely understood, such as the mechanics of reaction chemistry and the geometry of catalytic residues within active sites. As a result, the computational prediction of catalytic residues has the potential to identify novel catalytic pockets, aid in the design of more efficient enzymes and also predict the molecular basis of disease.
  
  
  RESULTS
  We propose a new kernel-based algorithm for the prediction of catalytic residues based on protein sequence, structure and evolutionary information. The method relies upon explicit modeling of similarity between residue-centered neighborhoods in protein structures. We present evidence that this algorithm evaluates favorably against established approaches, and also provides insights into the relative importance of the geometry, physicochemical properties and evolutionary conservation of catalytic residue activity. The new algorithm was used to identify known mutations associated with inherited disease whose molecular mechanism might be predicted to operate specifically though the loss or gain of catalytic residues. It should, therefore, provide a viable approach to identifying the molecular basis of disease in which the loss or gain of function is not caused solely by the disruption of protein stability. Our analysis suggests that both mechanisms are actively involved in human inherited disease.
  
  
  METHODS
  Source code for the structural kernel is available at www.informatics.indiana.edu/predrag/.
authors.affiliation: School of Informatics and Computing, Indiana University, Bloomington, IN 47408, USA.
authors.forename: Fuxiao
authors.initials: F
authors.lastname: Xin
authors.forename: Steven
authors.initials: S
authors.lastname: Myers
authors.forename: Yong Fuga
authors.initials: YF
authors.lastname: Li
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.forename: Predrag
authors.initials: P
authors.lastname: Radivojac
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001185:Artificial Intelligence; D002384:Catalysis; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D004798:Enzymes / Q000737:chemistry* / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D012984:Software
chemical_list: D004798:Enzymes; D011506:Proteins