Simulating induced fit in molecular docking

ABAGYAN, RUBEN A.; TOTROV, MAXIM; FERNANDEZ-RECIO, JUAN; KOVACS, JULIO A.; CAVASOTTO, CLAUDIO N.

Lyon

Workshop; CECAM Workshop on Flexible Macromolecular Docking; 2004

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 Calpha-model can be used to generate alternative conformations