Q‐Dock: Low‐resolution flexible ligand docking with pocket‐specific threading restraints

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Abstract
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 root‐mean‐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. J Comput Chem 2008