Table 1.

Techniques for incorporating full protein flexibility into docking approaches

Approach	Method for incorporation	Advantages	Limitations
Refinement	Flexibility introduced after docking through reduced or all-atom modeling with molecular dynamics or Monte Carlo minimization	Fast docking to rigid receptor enables searching through vast compound libraries	Unlikely to generate as much structural diversity as the other methods, hard to move beyond known binding space
Average or unified structure	Ensemble averaging through use of a unified structure or grid representation Can also occur through the selection of conformational subsets from a rotameric library May also involve generation of receptor conformations based on ligand poses	Can find novel binding mechanisms, orphan sites, and explore new receptor conformations	Discovery of ‘paradoxical inhibitors’ that bind only to averaged conformation but not a native structure
Serial docking	Docking performed iteratively to a rigid ensemble of structures, conformational variation of the receptor ensemble typically comes from the inclusion of several x-ray crystallography, NMR, homology model, PCA-derived, NMA-derived or MD-derived structures	Can allow for discovery of novel binding modes	Ensemble generation and parallel docking can be time-consuming, not usually appropriate for screening large libraries Structural variation can increase false positives
Conformations on the fly	Receptor conformational changes are explicitly modeled during docking	Allows receptor conformation to change during interaction with ligand for optimal binding, can be quite accurate	Can generate conformations that are not experimentally accessible Can be quite time-intensive, not necessarily appropriate for virtual screening