This tutorial describes the *basic* steps to setup a molecular docking calculation of a ligand onto a metal-organic framework (MOF) surface. The tutorial has been adapted from a previous tutorial “Using AutoDock 4 with AutoDockTools” by Garret Morris at The Scripps Research Institute (TRSI) that has been designed for ligand-protein systems. We will use a graphical interface called AutoDockTools (ADT) to set up the two molecules for the docking calculation.
Besides ADT the tutorial requires other softwares to be installed in your machine: AutoDock and AutoGrid, available from Art Olson’s group at TSRI (http://autodock.scripps.edu/), MarvinSketech (http://www.chemaxon.com/) and Mercury from the CCDC (http://www.ccdc.cam.ac.uk/). Please familiarize yourself with each program by reading the corresponding manuals.
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I. Setup of the small ligand structure
You will need to have the atomic coordinates of your ligand, i.e. its 3D structure. For that, you can either use experimentally obtained atomic coordinates or you can build the structure using a modeling or drawing software. In this tutorial we will use the free software MarvinScketch.
i. In the MarvinSkcetch interface, first draw you molecule, then go to the menu “Chemistry” and choose “Clean 2D” (If you made any mistake when drawing you molecule, the program will complain and you can fix it before going to the third step). If there are no complaints regarding the number of bonds or missing hydrogens, etc. you can go again to the menu “Chemistry”, choose “Build or Optimize”, and then in the same menu choose “Clean 3D”. Once you have drawn the structure save it as Tripos mol2 format.
ii. In the AutoDock Tools (ADT) graphical interface, go to the menu “File” and choose “Read molecule”. Pick the small molecule file (*mol2) that you have previously built with MarvinScketch. In the menu “Edit”, choose “Charges” and then “Compute Gasteiger”. To make sure that the total charge in the ligand is an integer, in the menu “Edit” choose “Check totals on residues”. Go to menu “Ligand”, select “Input”, then select “Choose” and click on the small ligand molecule in the pop-out window. In the menu “Edit” choose “Output” and save the coordinates as *pdbqt.
II. Setup of the MOF structure
i. In the Mercury interface, go to “File”, then “Open” and choose the MOF atomic coordinates in the format cif. Subsequently, go to “Calculate” and choose “Packing and Slicing”. In this window click on “pack” and on “Molecules where all atoms fit”. Choose the dimensions to grow your MOF surface by adjusting the values of axis a, b and c. Click on the button “OK” at the end of the window. Go again to menu “File” and then to “Save as”. Save the structure in the format pdb or Tripos mol2.
ii. In the ADT graphical interface, go to “File” and then “Read molecule”. Choose the atomic coordinates for your MOF and click “Open”. In the menu “Edit”, choose “Charges” and then “Compute Gasteiger”. To make sure that the total charge in the ligand is an integer, in the menu “Edit” choose “Check totals on residues”. Go to menu “Grid”, select “Macromolecule”, “Choose”, and then click on the MOF molecule in the pop-out window. Save the coordinates as *pdbqt.
III. Preparing the Grid Parameter File
In the ADT interface, go to “Set map types” and click on “Open ligand”. Choose the small ligand pdbqt file and then click on the button “Accept”. This step allows you to modify the types of maps to be calculated, and to choose whether to model possible hydrogen bonds or not. In the menu “Grid”, choose “Grid box”. Go to the submenu “Center” and choose “Pick an atom”. Then click on the atom where you would like to center the grid box. Adjust the number of points in the X, Y and Z dimensions by scrolling the corresponding thumbweel. The number of points in each dimension can be adjusted up to 126. AutoGrid requires that the input number of grid points be an even number. It then adds one point in each dimension, since AutoGrid and AutoDock need a central grid point. Then adjust the spacing between points. Go to the submenu “File” and choose “Close saving current”. In the menu “Grid”, choose “Output”. Save the file ligand.MOF.gpf.
IV. Running AutoGrid
In a shell terminal, run the command:
autogrid4 -p ligand.MOF.gpf -l ligand.MOF.glg &
In the machines of the BioMat Group, Autogrid and Autodock are installed under /usr/local/autodock/src/autogrid/ and /usr/local/autodock/src/autodock/.
V. Preparing the Docking Parameter File
There are four different docking algorithms currently available in AutoDock: SA, the original Monte Carlo simulated annealing; GA, a traditional Darwinian genetic algorithm; LS, local search; and GALS, which is a hybrid genetic algorithm with local search. The GALS is also known as a Lamarckian genetic algorithm, or LGA, because children are allowed to inherit the local search adaptations of their parents. In this tutorial, we will use the Lamarckian genetic algorithm.
In the ADT interface, go to the menu “Docking”, “Macromolecule and click on “Set rigid filename”. Choose the MOF pdbqt file and then click on the button “Open”. Still in the menu “Docking”, go to “Ligand” and click on “Choose”. Pick the small ligand and then click on “Accept”. In the “Docking” menu, go to “Search parameters”, choose “Genetic algorithm”, and click on the button “Accept”. In the first run for a system keep the number of GA runs = 10, the calculation will finish quickly and if there is something wrong with your setup you can correct it without much delay. In the “Docking” menu choose “Output”, then “Lamarckian GA” and save the file as ligand.MOF.dpf.
IV. Running AutoGrid
In a shell terminal, run the command:
autodock4 -p ligand.MOF.dpf -l ligand.MOF.dlg &
Please remember that this is a standard setup and most likely you will need to make different choices for your system. Please, read the manual to make sure you understand the options available in the program.