(The FASEB Journal. 2008;22:lb333)
© 2008 FASEB
A new method for ligand docking to flexible receptors by dual alanine scanning and refinement (SCARE)
Giovanni Bottegoni1,
Irina Kufareva1,
Maxim Totrov2 and
Ruben Abagyan1,2
1 Molecular Biology, The Scripps Research Institute, La Jolla, CA
2 Molsoft, LLC, La Jolla, CA
ABSTRACT
Protein binding sites undergo ligand specific conformational changes upon ligand binding. However, most docking protocols rely on a fixed conformation of the receptor or on the prior knowledge of multiple conformations representing the variation of the pocket. Here we described a general induced fit docking protocol that requires only one initial pocket conformation and identifies most of the correct ligand positions as the lowest score. The algorithm systematically scans pairs of neighbouring side chains, replaces them by alanines, and docks the ligand to each ‘gapped’ version of the pocket. All docked positions are scored, refined with original side chains and flexible backbone and re-scored. In the optimal version of the protocol pairs of residues were replaced by alanines and only one best scoring conformation was selected from each ‘gapped’ pocket for refinement. The optimal SCARE (SCan Alanines and REfine) protocol identifies a near native conformation (under 2Å RMSD) as the lowest rank for 80% of pairs if the docking bounding box is defined by the predicted pocket envelope, and for as many as 90% of the pairs if the bounding box is derived from the known answer with 
5 Å margin as used in most previous publications. Furthermore, the results for conformationally conserved pockets do not deteriorate due to substantial increase of the pocket variability.
