Knowledge-Guided Docking of Flexible Ligands to SH2 Domain Proteins

Studies of interactions between protein domains and ligands are important in many aspects such as cellular signaling and regulation. In this work, we applied a three-stage knowledge-guided approach of docking flexible peptide ligands to SH2 domains. The first stage of the approach search for binding pockets of SH2 domain proteins and binding motifs of peptide ligands based on known features. The knowledge of the binding sites are used in the second stage as binding constraints to align ligand's peptide backbone to the SH2 domain. The backbone-aligned ligands produced serve as good starting points to the third stage which uses a Monte Carlo method to perform the flexible docking. The experimental results show that the backbone alignment method at the second stage produces good backbone conformations which are close to the conformation in complex. The binding site information is well utilized to provide a better starting point to the next docking stage. The subsequent docking is successful or partially successful in 5 of 7 test cases. The performance is better than that of general docking methods. The presented approach can also be applied to other well characterized protein domains which bind ligands in two or more binding grooves.