COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 137
cally pooling relevant data. The expected surfeit of protein structures provides an opportunity to de-
velop computational methods for collectively examining multiple biological structures and extracting
key biophysical and biochemical features, as well as methods for automatically recognizing these fea-
tures in new protein structures.
Wei and Altman have developed an automated system known as FEATURE that statistically stud-
ies the important functional and structural sites in protein structures such as active sites, binding sites,
disulfide bonding sites, and so forth. FEATURE collects all known examples of a type of site from the
Protein Data Bank (PDB) as well as a number of control “nonsite” examples. For each of them, FEA-
TURE computes the spatial distributions of a large set of defined biophysical and biochemical proper-
ties spanning multiple levels of details in order to capture conserved features beyond basic amino acid
sequence similarity. It then uses a nonparametric statistical test, the Wilcoxin Rank Sum Test, to find the
features that are characteristic of the sites, in the context of control nonsites. Figure 5.3 shows the
statistical features of calcium binding sites.
By using a Bayesian scoring function that recognizes whether a local region within a three-dimen-
sional structure is likely to be any of the sites and a scanning procedure that searches the whole
structure for the sites, FEATURE can also provide an initial annotation of new protein structures.
FEATURE has been shown to have good sensitivity and specificity in recognizing a diverse set of site
types, including active sites, binding sites, and structural sites and is especially useful when the sites do
not have conserved residues or residue geometry. Figure 5.4 shows the result of searching for ATP
(adenosine triphosphate) binding sites in a protein structure.
FIGURE 5.2 A Computational Approach to Molecular Docking. SOURCE: Courtesy of A.N. Jain, University of
California, San Francisco.