Computational Chemistry Tutorial: 3. Building Molecules with MOLDEN
Building Molecules with MOLDEN
Ability to build molecular models with computers in an important skill for chemists who use computer-aided drug design. This tutorial illustrates how to edit and build molecular structures with MOLDEN. The last part of this tutorial illustrates how MOLDEN can be used to optimize molecular structures and prepare molecules for more advanced calculations.
MOLDEN allows building molecules using the connectivity description known as the Z-matrix. In the Z-matrix notation, the atoms in the molecule are defined by bond a length to one of the preceding atoms, by a bond angle made to two preceding atoms and by a dihedral angle made to three preceding atoms. MOLDEN's Z-matrix editor is explained in more detail at http://www.cmbi.ru.nl/molden/zmat/zmat.html.
Start MOLDEN by typing molden ethanol.pdb into Unix shell on the workstation. Two windows, the graphical area and the Molden Control appear. Turn on StickColor and try if the molecule looks better with Shade on or off.
Hit the ZMAT Editor button to open the Z-Matrix editor. Answer Yes if prompted to create a new Z-matrix. Inspect the Z-Matrix by clicking on each atom and observe how the selected atom is highlighted in the graphical window. It also works in reverse: clicking on an atom in the 3D structure will highlight this atom in the Z-matrix. Now click on the bond distances fields in the Z-Matrix editor and notice how the two connected atoms are highlighted. You can measure arbitrary distances easily using the Distance tool in the Molden Control panel. The Zmatrix editor in Molden is pretty simple to learn. The few rules that you should keep in mind when working with Z-matrixes are:
- The command Add Line adds a new atom in the molecule and creates a new line in the Z-matrix. The Substitute Atom by Fragment allows replacement of atoms with common functional groups. You may occasionally need to use Reorder Z-matrix to achieve desired symmetry or when needing to delete atoms that are used to define position of other atoms.
- When adding a new atom, click on the atom it is connected to, then on the atom it makes an angle with, then on the atom it forms dihedral angle with.
- When replacing an atom with fragment, click on the atom to be replaced, then select the fragment.
- You may adjust bond lengths and bond angles to reflect the local geometry of the molecule. For example, to draw the gauche form of ethanol, you may change the dihedral angle for the OH hydrogen (the HO-CC torsion) to 60 degrees.
- All bond angles should be less than 180 degrees. However, dihedral angles can have any value between -360 and +360.
- For highly symmetric molecules, or with molecules with linear groups (such as acetonitrile) use of dummy atoms to define the position of first few real atoms.
Oftentimes you have a structure that you want to modify slightly. For example, you may notice that more hydrophobic analogs of a drug are more potent and wish to create a higher homolog of your lead compound by extending or branching the alkyl chain. MOLDEN is well suited for such task. Please note that it is recommended to assign a SYBYL force field to the modified molecule every time before writing out a new structure as MOL2 file even if you are not planning to optimize the molecule. Follow the instructions below to create isopropanol (2-propanol) by modifying the structure of ethanol.
- Use Substitute Atom by Fragment function to replace one of the CH2 hydrogens with the methyl group. Notice how the new atoms appear in the Z-matrix editor and in the MOLDEN graphical window.
- Close the Z-matrix editor but do not exit MOLDEN.
- Click on the FF icon in the MOLDEN Control window. This brings up Molecular Mechanics Force Field tools that allow assignment of the force field atom types and optimization of molecular geometry. This feature works nicely with simple molecules but most likely you are not able to use MOLDEN/TINKER for automatic optimization of more complex organic molecules because of the lack of force field parameters.
- Select Tinker MM3 force field for optimization. The MM3 is one of many molecular mechanics force fields and is suitable for modeling simple organic compounds. Another useful force field is the Tripos/Sybyl force field that should be selected for molecules that you are not planning to minimize with TINKER.
- Click on OPT button. Change the Job name to isopropanol. Keep other settings at default values and press GO to optimize the structure.
- Inspect the optimized structure. Close MOLDEN; the optimized structure was saved on your directory in the file isopropanol.xyz.