Simulating induced fit in molecular docking.

Ruben Abagyan, Maxim Totrov, Juan-Fernandez Recio, 
Julio Kovacs, Claudio Cavasotto. 
The Scripps Research Institute, La Jolla.
 

The main complicating factor in molecular docking is receptor rearrangement upon ligand binding (induced fit).  It is the induced fit that complicates cross-docking of ligands from different ligand receptor complexes. To improve on discriminating between binders and nonbinders in the virtual screening process we developed a protocol which performs receptor-flexible docking of known ligands in order to simulate possible pocket rearrangements. This protocol was applied to a benchmark of kinases and was demonstrated to improve both the cross-docking accuracy as well as the "enrichment" in virtual ligand screening. In protein-protein docking and peptide protein docking the side-chain sampling may be sufficient to account for induced fit. The induced changes of the backbone are more problematic. We show how the slow modes of soft harmonic Ca-model can be used to generate alternative conformations.