AutoDock Version 4.2

Appendix II: Docking Flexible Rings with AutoDock1. IntroductionAutoDock is not able to manage directly the flexibility associated with bonds in cyclic molecules,which leads to cyclic portions of the ligands to be considered as rigid. Different approaches canbe used to dock macrocyclic molecules, like identifying one or more low energy conformationsand docking them as different ligands, but generating them and docking them separately can be atime-consuming task. As an alternative, an indirect method may be used to manage the ring as afully flexible entity and use the AutoDock GA to explore its flexibility. The method was initiallydeveloped for version 3.05, and now is implemented in version 4.2. The protocol converts thecyclic ligand into its corresponding acyclic form by removing a bond, and then docks the fullyflexible molecule in the open form. A special atom type definition allows AutoDock to restorethe original cycle structure during the calculation while exploring the cycle conformations withthe GA. The protocol can be subdivided in three main steps:: by removing a bond, the ring is opened and the ligand is transformedto an acyclic form. the ligand is processed following the standardAutoDockTools protocol, but the edge atoms are replaced with G atoms. : the ligand is docked applying a 12-2 pseudo-Lennard-Jones potential to the G-atoms that restore the cyclic structure.To restore the closed ring geometry a custom long range pseudo-Lennard-Jones 12-2 potential isapplied to these atoms during the docking calculation. This potential is effective at long rangedistances and guarantees the ring closure even with large cycles.44