Using AutoDock for Ligand‐Receptor Docking
互联网
1556
- Abstract
- Table of Contents
- Figures
- Literature Cited
Abstract
This unit describes how to set up and analyze ligand?protein docking calculations using AutoDock and the graphical user interface, AutoDockTools (ADT). The AutoDock scoring function is a subset of the AMBER force field that treats molecules using the United Atom model. The unit uses an X?ray crystal structure of Indinavir bound to HIV?1 protease taken from the Protein Data Bank (UNIT 1.9 ) and shows how to prepare the ligand and receptor for AutoGrid, which computes grid maps needed by AutoDock. Indinavir is prepared for AutoDock, adding the polar hydrogens, and partial charges, and defining the rotatable bonds that will be explored during the docking. The input files for AutoGrid and AutoDock are created, and then the grid map calculation run, followed by the docking calculation in AutoDock. Finally, this unit describes some of the ways the results can be analyzed using AutoDockTools. Curr. Protoc. Bioinform. 24:8.14.1?8.14.40. © 2008 by John Wiley & Sons, Inc.
Keywords: AutoDock; protein?ligand docking; virtual screening; computer?aided drug design
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online LibraryTable of Contents
- Introduction
- Basic Protocol 1: Download and Install AutoDock, AutoGrid, and AutoDockTools
- Basic Protocol 2: Preparing the Macromolecule
- Basic Protocol 3: Preparing the Ligand
- Basic Protocol 4: Saving the Macromolecule in PDBQT Format
- Basic Protocol 5: Preparing the Flexible Residues (Optional)
- Basic Protocol 6: Preparing the Grid Parameter File
- Basic Protocol 7: Starting AutoGrid 4
- Basic Protocol 8: Setting Up the Docking
- Basic Protocol 9: Starting AutoDock 4
- Basic Protocol 10: Reading Docking Logs
- Basic Protocol 11: Visualizing Docked Conformations
- Basic Protocol 12: Clustering Conformations
- Basic Protocol 13: Visualizing Conformations in the Complex
- Guidelines for Understanding Results
- Commentary
- Literature Cited
- Figures
- Tables
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online LibraryMaterials
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online LibraryFigures
-
Figure 8.14.1 The AutoDockTools graphical user interface (GUI) has two rows of menus; the upper row is for more generic operations, while the lower row are specific to AutoDockTools. This figure shows the Read Molecule file browser about to load hsg1.pdb; note that the file browser is set to show all file types. View Image -
Figure 8.14.2 The receptor molecule HIV‐1 protease from the PDB structure (1HSG) colored by atom type. View Image -
Figure 8.14.3 All hydrogen atoms have been added to HIV‐1 Protease. View Image -
Figure 8.14.4 The “root” of the torsion tree is shown as a (green) sphere with the rotatable bonds as green lines. Bonds that could rotate but are not set to be rotatable are shown as magenta lines, and bonds that cannot rotate are shown as red lines. In this case, only one atom would appear between the ROOT and ENDROOT records, while all the atoms moved by each rotatable bond would appear between appropriately‐labeled BRANCH and ENDBRANCH records. (These labels refer to the serial numbers of the two atoms involved in the rotatable bond.) View Image -
Figure 8.14.5 Part of a PDBQT file for the macromolecule used in this protocol, HIV protease. Note the last two columns, showing the partial atomic charge and the AutoDock 4 atom type for each atom. Abbreviations in last column: C, aliphatic carbon; H, hydrogen not capable of hydrogen‐bonding; HD, polar hydrogen able to donate hydrogen bond; N, nitrogen not capable of accepting a hydrogen bond; OA, oxygen capable of accepting a hydrogen bond. View Image -
Figure 8.14.6 Two Arg‐8 side chains have been selected to be flexible residues. Each selected atom is indicated with yellow crosses. Note that in the middle of the bottom row, the number of selected residues is shown in the box after the word Selected. View Image -
Figure 8.14.7 A close‐up of the rotatable bonds selected in the Arg‐8 sidechains. Three green rotatable bonds are set to be rotatable in each Arg‐8 side chain: CB‐CG, CG‐CD and CD‐CE. View Image -
Figure 8.14.8 It is possible to control the size of the AutoGrid box used to compute the grid maps using the Grid Options panel. The number of grid points can be changed by dragging on the thumbwheel, or by typing in the value and pressing Enter while the cursor is over the thumbwheel. Similarly, the grid point spacing in Å and the x,y,z coordinates of the center of the grid box can be specified using this panel. View Image -
Figure 8.14.9 The most important parameters for the Genetic Algorithm (GA) and Lamarckian Genetic Algorithm (LGA) are set in this panel. The number of independent docking runs, the size of the population, and how long each docking will run can be set here. The GA and LGA will terminate when either the maximum number of energy evaluations (evals) or the maximum number of generations is reached, whichever comes first. View Image -
Figure 8.14.10 A small excerpt from an AutoDock log file (DLG), with line numbers added for clarity. It shows the output at the beginning and end of a docking, and the beginning of the output of the docked ligand PDBQT file, each line of which is preceded by the string DOCKED:. The USER records give information about the number of the docking run, the docking parameter file (DPF) used, the estimated free energy of binding, an energy breakdown, and a description of the position, orientation, and conformation of the ligand. Much more information is present in the DLG, but cannot be shown in this figure. DLG files can be read in by AutoDockTools, which greatly facilitates the analysis of the dockings. View Image -
Figure 8.14.11 The docked conformations are listed in the lower part of the Conformation Chooser panel. They are named according to the rank of the cluster to which they belong and their rank in that cluster. Clicking on one of the entries in this list displays information about it in the upper panel; in this case, ind_1_1 has been selected, which is the lowest energy conformation in the lowest energy cluster. Double‐clicking on one of these entries updates the conformation of the ligand in the 3D viewer to the corresponding coordinates. View Image -
Figure 8.14.12 An interactive histogram. Clicking on a bar in the histogram links the conformations in the corresponding cluster to the player and updates the ligand to the coordinates of the lowest energy conformation in that cluster. View Image -
Figure 8.14.13 Open Set Play Options panel to change play options via the ampersand (&) button, and click on “Show Info” to open the “Conformation 1_1 info” widget. View Image -
Figure 8.14.14 The C2 symmetry of the binding site of HIV‐1 is reflected in these two symmetrically related docked conformations of Indinavir. View Image -
Figure 8.14.15 Indinavir docked into a pocket in HIV‐1. Here the molecular surface has been colored using DG colors, the ligand is displayed as ball‐and‐sticks, and the complex has been rotated using the middle mouse button to show the active site tunnel. In the DG color scheme (created by David Goodsell and available as a setting option in ADT and the related molecular viewer PMV), neutral oxygen and nitrogen atoms are pink and light blue, respectively, while charged oxygen and nitrogen atoms are red and dark blue, respectively. This has the effect of highlighting the charged parts of charged amino acids: the acidic side chains Asp and Glu appear red, while basic side chains Arg and Lys appear blue. View Image -
Figure 8.14.16 The “displayMSMS” widget is used to select specific molecular surfaces and set their visibility. Here the undisplay radio‐button is checked, so clicking on the OK button will result in undisplaying the molecular surface, which is named MSMS‐MOL. View Image -
Figure 8.14.17 The isocontour value to display can be set to −0.5 Kcal/mol by dragging the small blue triangle in the Visualize AutoGrid widget to the left, or by positioning the cursor over the entry to the left of the LINE check button and typing ‐0.5 followed by the Return or Entry key. View Image -
Figure 8.14.18 Building new molecules can show all of the docked conformations in a cluster simultaneously for each one. In the Set Play Options widget, click on Build All. Use the Color > By Molecules menu option to differentiate among the docked structures. View Image
Videos
Literature Cited
| Literature Cited | |
| Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N., and Bourne, P.E. 2000. The Protein Data Bank. Nucleic Acids Res. 28:235‐242. | |
| Chen, Z., Li, Y., Chen, E., Hall, D.L., Darke, P.L., Culberson, C., Shafer, J.A., and Kuo, L.C. 1994. Crystal structure at 1.9‐Å resolution of human immunodeficiency virus (HIV) II protease complexed with L‐735,524, an orally bioavailable inhibitor of the HIV proteases. J. Biol. Chem. 269:26344‐26348. | |
| Cole, J.C., Murray, C.W., Nissink, J.W., Taylor, R.D. and Taylor, R. 2005. Comparing protein‐ligand docking programs is difficult. Proteins 60:325‐332. | |
| Cozzini, P., Kellogg, G.E., Spyrakis, F., Abraham, D.J., Costantino, G., Emerson, A., Fanelli, F., Gohlke, H., Kuhn, L.A., Morris, G.M., Orozco, M., Pertinhez, T.A., Rizzi, M., and Sotriffer, C.A. 2008. Target flexibility: An emerging consideration in drug discovery and design. J. Med. Chem. 51:6237‐6255. | |
| Gasteiger, J. and Marsili, M. 1978. A new model for calculating atomic charges in molecules. Tetrahedron Lett. 34:3181‐3184. | |
| Goodsell, D.S. and Olson, A.J. 1990. Automated docking of substrates to proteins by simulated annealing. Proteins 8:195‐202. | |
| Hetenyi, C. and van der Spoel, D. 2002. Efficient docking of peptides to proteins without prior knowledge of the binding site. Protein Science 11:1729‐1737. | |
| Hetenyi, C. and van der Spoel, D. 2006. Blind docking of drug‐sized compounds to proteins with up to a thousand residues. FEBS Lett. 580:1447‐1450. | |
| Huey, R., Morris, G.M., Olson, A.J., and Goodsell, D.S. 2007. A semi‐empirical free energy force field with charge‐based desolvation. J. Comput. Chem. 28:1145‐1152. | |
| Kontoyianni, M., McClellan, L.M. and Sokol, G.S. 2004. Evaluation of docking performance: Comparative data on docking algorithms. J. Med. Chem. 47:558‐565. | |
| Kontoyianni, M., Madhav, P., Suchanek, E. and Seibel, W. 2008. Theoretical and practical considerations in virtual screening: A beaten field? Curr. Med. Chem. 15:107‐116. | |
| Leach, A.R., Shoichet, B.K. and Peishoff, C.E. 2006. Prediction of protein‐ligand interactions. Docking and scoring: Successes and gaps. J. Med. Chem. 49:5851‐5855. | |
| Lin, J.H., Perryman, A.L., Schames, J.R., and McCammon, J.A. 2002. Computational drug design accommodating receptor flexibility: The relaxed complex scheme. J. Am. Chem. Soc. 124:5632‐5633. | |
| Lin, J.H., Perryman, A.L., Schames, J.R., and McCammon, J.A. 2003. The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme. Biopolymers 68:47‐62. | |
| McCammon, J.A. 2005. Target flexibility in molecular recognition. Biochim. Biophys. Acta 1754:21‐24. | |
| Morris, G.M., Goodsell, D.S., Huey, R., and Olson, A.J. 1996. Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4. J. Comput. Aided Mol. Des. 10:293‐304. | |
| Morris, G.M., Goodsell, D.S., Halliday, R.S., Huey, R., Hart, W.E., Belew, R.K., and Olson, A.J. 1998. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 19:1639‐1662. | |
| Sanner, M.F., Olson, A.J., and Spehner, J.C. 1996. Reduced surface: An efficient way to compute molecular surfaces. Biopolymers 38:305‐320. | |
| Schames, J.R., Henchman, R.H., Siegel, J.S., Sotriffer, C.A., Ni, H., and McCammon, J.A. 2004. Discovery of a novel binding trench in HIV integrase. J. Med. Chem. 47:1879‐1881. | |
| Shoichet, B.K., McGovern, S.L., Wei, B., and Irwin, J.J. 2002. Lead discovery using molecular docking. Curr. Opin. Chem. Biol. 6:439‐446. | |
| Sousa, S.F., Fernandes, P.A., and Ramos, M.J. 2006. Protein‐ligand docking: Current status and future challenges. Proteins 65:15‐26. | |
| Vaque, M., Arola, A., Aliagas, C., and Pujadas, G. 2006. BDT: An easy‐to‐use front‐end application for automation of massive docking tasks and complex docking strategies with AutoDock. Bioinformatics 22:1803‐1804. | |
| Warren, G.L., Andrews, C.W., Capelli, A.M., Clarke, B., LaLonde, J., Lambert, M.H., Lindvall, M., Nevins, N., Semus, S.F., Senger, S., Tedesco, G., Wall, I.D., Woolven, J.M., Peishoff, C.E., and Head, M.S. 2006. A critical assessment of docking programs and scoring functions. J. Med. Chem. 49:5912‐5931. |
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library
