Download Building small molecules

Building small molecules
Use the Builder (right panel) to build up molecules.
Start building clicking a fragment/atom in the builder and it will
appear to the workspace. Continue modifying the molecule by
selecting atom(s) or bonds that you want to modify and use
fragments/atoms/bonds from the builder.
Hint (selection):
-
Left-click to select an atom.
You can also select bonds by clicking them.
Hold shift to select multiple atoms.
Ctrl+left-click to select whole molecule or residue.
Double-click to select whole molecule or protein.
1. Build the following molecules (5), minimize and save
them (.moe -format)
Remember to Minimize your molecules in the end.
Save your molecule and clear the workspace (with Close on right
panel) before starting to build another molecule.
Celecoxib
Indomethacin
Note: build the –COOH group as –COO(Normally this would appear after proper structure
preparation, due to time limits we do it in a quick way)
INTEGRATE SUMMER SCHOOL 7.6.2016
Alprazolam
Phenoxymethylpenicillin
Note the chirality and -COOH!
Hint (chirality):
-
You can change the chirality by selecting a chiral atom and modifying its chirality (R/S) from
the builder, and after the minimization chirality changes accordingly.
Tetracycline
*Note the chirality!
INTEGRATE SUMMER SCHOOL 7.6.2016
Examine
properties /
visualization of
small molecules
Open up one of the built
*.moe ligand-file that you
want to examine more deeply.
Try out different
representations for the
molecule and colors…
Select whole molecule, right-click:
Atoms
e.g. Label: Charge gives you the point
charges of the atoms
Next, examine properties of the
molecule with special surfaces.
Go to (right panel)
Surface
Surfaces and Maps…
e.g. You can get the Molecular
surface colored by lipophilicity with
these settings:
Hint: you can adjust the transparency
of a surface (front/back) from here
Try out premade visualization themes.
E.g. the figure above is represented by Schematic
theme.
INTEGRATE SUMMER SCHOOL 7.6.2016
Small molecule database
You will need to combine your built molecules in a database for tomorrows docking exercise.
1. Create a combined molecular database from your ligands.
New
Database…
New Database window opens up. Name your database e.g. ligands and save it (*.mdb).
Database Viewer window opens up. As you see it is empty. Now, add your molecules to the
database.
File
Import…
Add…
Double click all your molecules to add them
to the list
OK
OK
Now, you should see your molecules in your
Database Viewer
You can expand the cells to see the 2D-structures by
dragging from the down-right corner of the cell.
Save it in .mdb –format. (You need to type .mdb in
the filename)
INTEGRATE SUMMER SCHOOL 7.6.2016
Protein preparation
1. Retrieve a human Lysozyme C structure
You can download directly RCSB PDB structures in MOE.
Go to
File…
Open…
RCSB PDB (left panel)
type 2NWD (PDB ID) to Codes:
Click OK
After the downloading is finished, there opens up a new interactive Load PDB File window. You
can use the default settings, press OK
Show all atoms
As you see (e.g. from waters) that you need to prepare the structure.
Use QuickPrep (right panel)
Set Tether Receptor Strength
1000 and uncheck Fix Atoms…
Click OK
You can see how atoms move
and orient during the minimization
process.
INTEGRATE SUMMER SCHOOL 7.6.2016
Now you have prepared the protein and it is ready for further
analysis.
Next, you will train how to hide/show specific residues.
2. Visualize all disulfide bridges of Lysozyme C
You are interested in Lysozymes disulfide bridges, and where they
are located. Breakage of these important bonds will result in
Lysozyme’s denaturation.
Hide all unnecessary information and visualize disulfide bridges in a
clear way (example fig.). Label them as well.
From Ribbon you may change the style and color for the ribbon.
Open up the Sequence Editor from SEQ (up-right) to make
selections from sequence.
Hint (sequence editor):
-
for selecting residues/chains from SEQ see that you have Select
box checked
double-click chain name (on left) to select whole chain
Synchronize –
-
change display settings (e.g. one or three letter codes for amino acids) from down-right
Visualize your result:
Render…
Setup…
Save Picture…
The checklist for visualization
Starting point: What do you want to say with the figure?
Remove all unnecessary “information” from the figure.
o Hide nonpolar hydrogens!
Center to the point of interest.
Labeling.
Use colors (discreetly & sensibly), surfaces, shapes, clipping, fog, focal blur etc. to make
your statement more clear.
Check that the atoms are unselected in the workspace (you don’t want to have a pink atom
selection in the final figure!)
Adjust the resolution according to your needs
CMYK colors for publications
INTEGRATE SUMMER SCHOOL 7.6.2016
3. Prepare K-Ras protein in complex with a GTP-analog
Download 3GFT structure
File…
Open…
3GFT (PDB ID)
(Default settings)
K-Ras is biologically active as a monomer, however, how many K-Ras proteins you find in the
structure? Why?
Are all chains totally similar, are there more disordered regions (missing residues) in some chains
than in others?
Check out the ligands in chain F, what is the additional ligand is this chain and why it’s there?
Obviously, you cannot prepare a structure like this. There is, for example, two options how to
prepare the structure:
1) Delete all other chains except one, and all unnecessary “things” from the selected chain as
well
OR
2) Download the structure again (Close workspace before) and use the setting in
Load PDB File
Symmetry: Biomolecule
This option will download only a biologically active unit.
Now you can prepare the protein with: QuickPrep
Tether Receptor Strength 1000 and use Fix Atoms… option
Investigate the ligand (GTP) interactions with the protein.
What kind of interactions are present?
You can generate a 2D-interaction diagram from: Compute
Ligand interactions…
To isolate view only for ligands binding site use: SiteView (right-panel)
INTEGRATE SUMMER SCHOOL 7.6.2016