Homology model directed alignment selection for comparative molecular field analysis: Application to photosystem II inhibitors

The use of a computational docking protocol in conjunction with a protein h omology model to derive molecular alignments for Comparative Molecular Fiel d Analysis (CoMFA) was examined. In particular, the DOCK program and a mode l of the herbicidal target site, photosystem II (PSII), was used to derive alignments for two PSII inhibitor training sets, a set of benzo- and naptho quinones and a set of butenanilides. The protein design software in the QUA NTA molecular modeling package was used to develop a homology model of spin ach PSII based on the reported amino acid sequence and the X-ray crystal st ructure of the purple bacterium reaction center. The model is very similar to other reported PSII protein homology models. DOCK was then used to deriv e alignments for CoMFA modeling by docking the inhibitors in the PSII bindi ng pocket. The molecular alignments produced from docking yielded highly pr edictive CoMFA models. As a comparison, the more traditional atom-atom alig nments of the same two training sets failed to produce predictive CoMFA mod els. The general utilities of this application for homology model refinemen t and as an alternative scoring method are discussed.