How to build a small molecule
1 Introduction
2 What's you need
3 The molecule to build
4 Building the molecule
5 Structure optimization
6 Conformational search
1 Introduction
This tutorial explains how to build a small molecule (e.g. a ligand) using
the 3D molecular editor included in VEGA ZZ and how to perform a systematic
conformational search (grid scan) in order to find the best conformer.
2 What you need
- VEGA ZZ release 2.0.8 or greater (click here for the
software setup).
3 The molecule to build
Imagine that you want to build imipramine using the 3D molecular editor:

Imipramine
The editor is based on fragment databases containing building blocks that
can be combined each other to complete a more complex structure. For this
reason, you must cut the molecule in less complex fragments that will be
assembled as indicated in the following scheme:

Excluding initially the heteroatoms, the molecule can be fragmented in a tricyclic system (Dibenzo[a,d]cycloheptane), in a n-butyl chain and in
two methyl groups.
4 Building the molecule
- Select Edit
Add
Fragments in
main menu and
Add fragment/s window will appear.
- Choose Rings (aromatic) in Group box and
15 5H-Dibenzo[a,d]cycloheptane in
Fragment box.
- Click Finish and thus Close.
The starting building block is shown in the workspace:

- In order to change the C5 carbon to a nitrogen and to remove one hydrogen
connected to it, select Edit
Change
Atom/residue/chain in menu bar.
- Click C5 as indicated by the red arrow in the following picture:

- In Element field of Edit dialog, change C to
N, click Apply and close the window. The atom color
will change from green to blue.
- Rotating the molecule, highlight the two hydrogens bonded to N5.
- To remove one hydrogen, select Edit
Remove
Atom and click the atom to remove as indicated by the red
arrow:

The hydrogen will be deleted. Click Done to close the
window.
- To add the n-butyl chain, reopen the Add fragment/s window (Edit
Add
Fragments), search 04C n-Butane
in the Alkanes group and click Next button.
- Click the butane hydrogen that will be merged with the hydrogen bonded to
N5 (see red arrow):

- Click Next button and the tricyclic system will be shown. Click
the hydrogen bonded to N5:

- Click the Next and thus Finish. Close the
window.
- As previously explained, you must change the C4 of the n-butyl
chain to a nitrogen and remove a hydrogen: select
Edit
Change
Atom/residue/chain and click the C4 as indicated by
the red arrow in the picture:

- In the Element field of the Edit dialog, change C to
N, click the Apply button and close the window.
- To remove one hydrogen, select Edit
Remove
Atom and click the atom to remove:

Click Done to close the window.
- Finally you must add two methyl groups to N4 of the n-butyl
chain. Open the Add fragment/s window (Edit
Add
Fragments).
- In Alkanes group select 01C Methane and click
Next.
- Click a methane hydrogen and Next button.
- Click a hydrogen of the ammine:

- Click Next and Finish.
- Repeat the same steps to add the second methyl group:

- Save the molecule in IFF format (File
Save
As...) with imipramine.iff name.
5 Structure optimization
In this section will be explained how to perform a conjugate gradient
minimization in order to optimize the rough 3D structure.
- Fix the atom types and the charges (Calculate
Charge & Pot.), checking Force field and Charges and selecting
SP4 and Gasteiger. Click Fix button. The total charge
is 0.
- Open the Ammp minimization
window selecting Calculate
Ammp
Minimization in the menu bar.
- Choose Conjugate gradients and set Minimization steps to
1000 and Toler to 0.01.
- Click Run button. After few steps, the minimization is
completed.
- Save the molecule in IFF format overwriting the previous one.
6 Conformational search
In order to find a reasonable lowest energy conformation, it will be
explained how to perform the conformational search of the built molecule. The
flexible torsions (dihedrals) will be systematically rotated by an angle value (grid
scan) and each conformation will be optimized in order to find the
best minimum.
- Open Ammp conformational search
window (Calculate
Ammp
Conformational search).
- Click Edit torsion button. The Selection
tool window will appear.
- In its menu bar, select Edit
Add flexible torsions and all
flexible torsion are automatically added in the selection list (4 torsions).
They are highlighted in the workspace also.
- Click Done button and the Ammp conformational search window is
shown.
- Select Systematic in Method field of Search
parameters box. The upper box shows the torsions that will be rotated during the scan.
Increasing the number of rotation steps (see the Steps field in
Torsion parameters box), the search is more accurate but more
computational time is required. The six value is a good choice because it
means a rotation 60 degrees of each step that in some cases is the threshold
to classify different conformations.
- Check Minimize all conformations and put 100 in the Steps
field and 0.01 in the Toler field. In this way, each conformation is
optimized using the conjugate gradients method. The minimization
finishes when the specified number of iterations (Steps) is reached or
the Toler condition is satisfied.
- If you want to analyze all conformations generated by the systematic search,
check Trajectory, Output and Energy in the left box.
Please remember to set the Graphic update to 1, otherwise not all
conformations will be stored in the output files. If you don't save the outputs,
only the lowest energy conformation is kept at the end of the calculation.
- Click Run button to start the calculation. In the console is
reported for each conformation the starting energy, the best energy found at
that time, and the energy after the minimization.
- After few time, the
search is finish and the best conformation is automatically loaded in the
workspace.
- To refine this structure, repeat the energy minimization as explained in
the previous section and save the final molecule.