Prediction of deleterious functional effects of amino acid mutations using a library of structure-based function descriptors.
An automated, active site-focused, computational method is described for use in predicting the effects of engineered amino acid mutations on enzyme catalytic activity. The method uses structure-based function descriptors (Fuzzy Functional Forms trade mark or FFFs trade mark ) to automatically identify enzyme functional sites in proteins. Three-dimensional sequence profiles are created from the surrounding active site structure. The computationally derived active site profile is used to analyze the effect of each amino acid change by defining three key features: proximity of the change to the active site, degree of amino acid conservation at the position in related proteins, and compatibility of the change with residues observed at that position in similar proteins. The features were analyzed using a data set of individual amino acid mutations occurring at 128 residue positions in 14 different enzymes. The results show that changes at key active site residues and at highly conserved positions are likely to have deleterious effects on the catalytic activity, and that non-conservative mutations at highly conserved residues are even more likely to be deleterious. Interestingly, the study revealed that amino acid substitutions at residues in close contact with the key active site residues are not more likely to have deleterious effects than mutations more distant from the active site. Utilization of the FFF-derived structural information yields a prediction method that is accurate in 79-83% of the test cases. The success of this method across all six EC classes suggests that it can be used generally to predict the effects of mutations and nsSNPs for enzymes. Future applications of the approach include automated, large-scale identification of deleterious nsSNPs in clinical populations and in large sets of disease-associated nsSNPs, and identification of deleterious nsSNPs in drug targets and drug metabolizing enzymes.
Herrgard
Sanna
S
Cengent Therapeutics, Inc., San Diego, California 92121, USA.
Cammer
Stephen A
SA
Hoffman
Brian T
BT
Knutson
Stacy
S
Gallina
Marijo
M
Speir
Jeffrey A
JA
Fetrow
Jacquelyn S
JS
Baxter
Susan M
SM
D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results
D000596:Amino Acids; D029968:Escherichia coli Proteins; D011506:Proteins; D001219:Aspartate Aminotransferases