VEGA ZZ tutorial - How to build a small molecule

How to build a small molecule

1. Introduction
2. What's you need
3. The molecule to build

3.1 PubChem download

3.2 IUPAC builder

3.3 SMILES builder

3.4 Ketcher 2D editor

3.5 3D molecular editor
4. Structure optimization
5. Conformational search

6. Final optimization

1. Introduction

This tutorial explains how to build a small molecule (e.g. a ligand) by using the 2D and 3D molecular editors 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 3.0.2 or greater (click here for the software setup).
MOPAC 2012 (optional, click here to know how to install it)

3. The molecule to build

VEGA ZZ includes some molecular editors with different features. The most intuitive editors are 2D, because you can build a molecule as shown on a paper sheet, but the most powerful is 3D, because allows you to change the molecules directly in the workspace with a total control of stereochemistry and geometrical isomerism. Moreover, VEGA ZZ can build molecules starting from their 1D structures from SMILES strings or IUPAC names, but these editors are not so intuitive. Finally, if you are lucky, you can download the 3D structure from PubChem database and show it in the VEGA ZZ environment.

For example, imagine you want to build imipramine or 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine:

Imipramine 2D structure
Imipramine

3.1 PubChem download

The easiest way to obtain a small molecule is to download it from PubChem library. VEGA ZZ includes the possibility to do that without the use of a Web browser.

Select File Download From PubChem and put imipramine in Molecule name to download.
Click Ok and the molecule will be downloaded from PubChem and shown in the current workspace.

3.2 IUPAC builder

If you know the 1D structure as IUPAC name of a small molecule, you can try to build it directly by using this information.

Select Edit Build IUPAC and IUPAC window will be shown.
Put 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine in the IUPAC name field and click Build.
The molecule will be converted to 3D and shown in the current workspace.

3.3 SMILES builder

Another possibility to build a molecule from 1D structure is the use of its SMILES string.

Select Edit Build SMILES and SMILES window will be shown.
Put CN(C)CCCN1C2=CC=CC=C2CCC3=CC=CC=C31 in SMILES field and the 2D preview will be automatically shown to allow you the correctness of the string.
Click Build and the molecule will be converted to 3D and shown in the current workspace.

3.4 Ketcher 2D editor

VEGA ZZ package includes a 2D molecular editor named Ketcher provided by GGA Software Services. It's very intuitive and easy to use.

Select Edit Ketcher and the editor window will be shown.
To build imipramine, start adding the cycloheptane ring by selecting it in the menu which is shown by clicking two times (a long double click) with the left mouse button on the icon shown as a benzene ring. Then, place the ring at center on the Ketcher edit area by clicking with the left mouse button.
Select benzene as above and add the two benzene rings by clicking the cycloheptane bonds.
Change the order (from single to double) of both bonds shared by benzene rings and cycloheptane in order to revert the aromaticity. To do it, click the two bonds and the bond order will be changed from single to double.
Click N in the element bar at the right in Ketcher window and click the carbon 1 of the cycloheptane to change it to nitrogen.
Add the n-butyl chain to the nitrogen by clicking the straight line of the tool bar on the left and the nitrogen. A single methyl will be added. Click the carbon of this methyl to add a second one and so on to obtain the n.-butyl chain.
As above, change the last carbon of the n-butyl chain to nitrogen and add two methyl groups to it.
The 2D structure is now finished. Click Send to VEGA ZZ to build the 3D structure.

3.1 3D molecular editor

Imagine you want to build imipramine using the 3D molecular editor. 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:

Imipramine fragments

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.

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:

The first building block

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:

Atom to click

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:

Hydrogen to remove

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):

Butane hydrogen to click

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

Hydrogen to click

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:

Carbon to click

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:

Hydrogen 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:

Ammine hydrogen to click

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

Final 3D structure

Save the molecule in IFF format (File Save As...) with imipramine.iff name.

4. 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.

5. 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.

6. Final optimization

If the molecular mechanics is not enough for you, you can perform a final optimization by semi-empirical calculation such as MOPAC.

Select Calculate Mopac and the MOPAC dialog window will be shown.
Click the Default button.
In the Parameters box, choose PM7 as calculation type if you have installed MOPAC 2012, otherwise choose PM1.
Leave the other parameters to default and click Run.
When the calculation is finished, the optimized structure is automatically loaded and you can save it in your preferred file format.