The rapidly growing number of theoretically predicted protein structures requires robust methods that can utilize low-quality receptor structures as targets for ligand docking. Typically, docking accuracy falls off dramatically when apo or modeled receptors are used in docking experiments. Low-resolution ligand docking techniques have been developed to deal with structural inaccuracies in predicted receptor models. In this spirit, we describe the development and optimization of a knowledge-based potential implemented in Q-Dock, a low-resolution flexible ligand docking approach. Self-docking experiments using crystal structures reveals satisfactory accuracy, comparable with all-atom docking. All-atom models reconstructed from Q-Dock's low-resolution models can be further refined by even a simple all-atom energy minimization. In decoy-docking against distorted receptor models with a rootmean-square deviation, RMSD, from native of ∼3 Å, Q-Dock recovers on average 15-20% more specific contacts and 25-35% more binding residues than all-atom methods. To further improve docking accuracy against low-quality protein models, we propose a pocket-specific protein-ligand interaction potential derived from weakly homologous threading holo-templates. The success rate of Q-Dock employing a pocket-specific potential is 6.3 times higher than that previously reported for the Dolores method, another low-resolution docking approach. © 2008 Wiley Periodicals, Inc.
Publication Source (Journal or Book title)
Journal of Computational Chemistry
Brylinski, M., & Skolnick, J. (2008). Q-dock: Low-resolution flexible ligand docking with pocket-specific threading restraints. Journal of Computational Chemistry, 29 (10), 1574-1588. https://doi.org/10.1002/jcc.20917