SiteBinder: An Improved Approach for Comparing Multiple Protein Structural Motifs

There is a paramount need to develop new techniques and
tools that
will extract as much information as possible from the ever growing
repository of protein 3D structures. We report here on the development
of a software tool for the multiple superimposition of large sets
of protein structural motifs. Our superimposition methodology performs
a systematic search for the atom pairing that provides the best fit.
During this search, the RMSD values for all chemically relevant pairings
are calculated by quaternion algebra. The number of evaluated pairings
is markedly decreased by using PDB annotations for atoms. This approach
guarantees that the best fit will be found and can be applied even
when sequence similarity is low or does not exist at all. We have
implemented this methodology in the Web application SiteBinder, which
is able to process up to thousands of protein structural motifs in
a very short time, and which provides an intuitive and user-friendly
interface. Our benchmarking analysis has shown the robustness, efficiency,
and versatility of our methodology and its implementation by the
successful superimposition of 1000 experimentally determined structures
for each of 32 eukaryotic linear motifs. We also demonstrate the applicability
of SiteBinder using three case studies. We first compared the structures
of 61 PA-IIL sugar binding sites containing nine different sugars,
and we found that the sugar binding sites of PA-IIL and its mutants
have a conserved structure despite their binding different sugars.
We then superimposed over 300 zinc finger central motifs and revealed
that the molecular structure in the vicinity of the Zn atom is highly
conserved. Finally, we superimposed 12 BH3 domains from pro-apoptotic
proteins. Our findings come to support the hypothesis that there is
a structural basis for the functional segregation of BH3-only proteins
into activators and enablers.