Jack Collins and I have been working on a procedure to dock putative
substrates into the active site of enzymes. The general procedure
is as follows.
- Obtain/construct a model of the enzymatic active site. (Jack)
- "Fill" the cavity with a cubic grid of points. (Jack)
- Add hydrogens to the protein and pre-load each grid point with ECEPP/2
electrostatic, H-bond, and Van der Waal terms. (Me)
- Take the putative substrate(s) and perform conformational searches
using Mopac7. Construct a database of low-energy conformations that
includes ECEPP/2 atom types and Mopac7 partial charges. (Me)
- Dock each conformation in the database into the grid that represents
the active site (Evol. Prog. with increasing "protein presence" followed
by local minimization of the best N results). (Me)
- Graphically display/analyze the results. (Jack)
The docking procedure is relatively fast (appx. 2 sec. per database
structure). Multiple docked results are obtained to show any
flexibility in the interaction. This method produced novel insights
into the interaction of captothecin and its derivatives with Human
Topoisomerase I.
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