AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility

Abstract

We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.

Figure 1. Redocking results

Results of redocking of 188 diverse ligand-protein complexes. Open squares represent complexes where the docked conformation with best predicted energy was less that 3.5Å RMSD relative to the experimentally observed conformation. Dots are complexes where the best docked conformation was greater than 3.5Å RMSD from the experimental structure.

Figure 2. Cross docking results

(A) Difference in energy between rigid docking and flexible docking. White points are docking experiments where the flexible docking showed 20 kcal/mol more favorable predicted free energy of docking and black points are docking experiments where the rigid docking showed similar or worse free energy of docking. Inhibitors are ordered from small to large, with the cyclic urea inhibitors separated at the bottom. The protease structures are ordered similarly. (B) Cross docking with rigid protease structures. Each point is colored by the RMSD of ligand atoms from the crystallographic structure, with RMSD=0 Å in white and RMSD>5 Å in black. (C) Cross docking with ARG8 treated as flexible in the protease. Each point is colored with the same scale as in (B).

Figure 2. Cross docking results

(A) Difference in energy between rigid docking and flexible docking. White points are docking experiments where the flexible docking showed 20 kcal/mol more favorable predicted free energy of docking and black points are docking experiments where the rigid docking showed similar or worse free energy of docking. Inhibitors are ordered from small to large, with the cyclic urea inhibitors separated at the bottom. The protease structures are ordered similarly. (B) Cross docking with rigid protease structures. Each point is colored by the RMSD of ligand atoms from the crystallographic structure, with RMSD=0 Å in white and RMSD>5 Å in black. (C) Cross docking with ARG8 treated as flexible in the protease. Each point is colored with the same scale as in (B).

Figure 2. Cross docking results

(A) Difference in energy between rigid docking and flexible docking. White points are docking experiments where the flexible docking showed 20 kcal/mol more favorable predicted free energy of docking and black points are docking experiments where the rigid docking showed similar or worse free energy of docking. Inhibitors are ordered from small to large, with the cyclic urea inhibitors separated at the bottom. The protease structures are ordered similarly. (B) Cross docking with rigid protease structures. Each point is colored by the RMSD of ligand atoms from the crystallographic structure, with RMSD=0 Å in white and RMSD>5 Å in black. (C) Cross docking with ARG8 treated as flexible in the protease. Each point is colored with the same scale as in (B).

Figure 3. Results of covalent docking

(A) Using a Gaussian map centered on serine OG. The crystallographic structure is shown in large bonds and the best docked conformation is shown in thinner bonds. The blue sphere surrounds the region of most favorable energy in the Gaussian map. (B) Using a Gaussian map centered on serine CB. (C) Using two Gaussian maps. (D) Using a flexible sidechain to model the covalent ligand.