CH3F5 Workshop 2: Biological Examples
Task 1: Vancomycin complexed to D-Ala-D-Ala
Aim: To produce a short report illustrated by one or two 3D pictures using Rasmol or Jmol on how
hydrogen bonds or other interactions are important in the recognition of the cell wall sequence D-Ala-DAla by the antibiotic vancomycin.
The instructions below are for Jmol.
Search for 1fvm.pdb in the Protein Databank and click on the option to view in Jmol.
In the window one vancomycin molecule and its bound substrate Lys-D-Ala-D-Ala are visible.
To measure the distance between atoms, double click on the first atom. Now as you touch other atoms,
the distance will be shown as a red line connecting the atoms. Double click on a second atom to fix the
distance report.
If you wish to cancel without fixing a distance report, simply move the mouse outside of the Jmol
rectangle. If you wish to remove one already fixed report, double click on each of those two atoms
again. If you wish to remove all distance reports, click the View button to refresh the molecular view.
You may also measure angles and dihedral angles by double-clicking on three or four atoms,
respectively.
Measure the distance between N-H and carbonyl groups by double-clicking on pairs of atoms whose
proximity you wish to investigate.
To display a list of the measurements you have taken, right-click on the Jmol window and select
Measurements > List Measurements
The standard Toggle H-Bonds button may not recognise all the relevant hydrogen bonds in the complex
unfortunately.
However we can work around this by first typing <set hbondsRasmol false> into the Jmol Script box.
Now the Toggle H-Bonds button will display the hydrogen bonds between vancomycin and the peptide
substrate (as well as some hydrogen bonds between vancomycin and water).
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Produce a graphical output file (.gif) using the Export Image button which clearly shows the antibiotic
complexed to the peptide substrate in sticks or backbone format. Using the select and colour commands
differentiate between the antibiotic and substrate.
Remember that you can type Rasmol commands into the Jmol Script box or alternatively, right click on
the image and choose the appropriate Select, Style>Scheme, and Colour options from the menus that
appear.
Now produce a similar picture which shows the antibiotic in spacefilling format with the antibiotic and
its peptide substrate clearly differentiated by colour.
Finally prepare a short report (about 1 page) including these pictures which explains where the key
hydrogen bonds are that play a role in stabilising the antibiotic-substrate complex. Where possible use
the codes from the PDB
Task 2: Aricept complexed to acetylcholinesterase (Structure 1eve.pdb)
Figure 1 Binding mode of Aricept within the active site of acetylcholinesterase.
Aricept is in clinical use for the treatment of Alzheimer’s disease through the inhibition of
acetylcholinesterase, an enzyme key to neuronal transmission. The drug binds to the active site of the
enzyme using the interactions in the diagram shown above to provide binding complementarity (see
Diederich et al. ACIEE 2003, 42, (11), 1210 for more details). Produce one or two 3D pictures showing
the inhibitor Aricept (code E20 2001 in 1eve.pdb) and its interactions with neighbouring amino acid
sidechains using Rasmol or Jmol (the instructions below are for Jmol). In order to do this you will need
to:
Search for the file 1eve.pdb in the Protein Databank and view in Jmol.
Restrict the display to the inhibitor only by right-clicking on the Jmol window and choose
Select>Hetero>By HETATM> followed by the inhibitor from the menus and then ensure that
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Select>Display Selected Only is checked. You will find it helpful to look at the text file of 1eve.pdb in
order to do this – you need to identify what the molecule codes correspond to.
Show the inhibitor as CPK Spacefill for example. Then display the enzyme as wireframe in a different
colour through the menu Select, Style and Colour options. (To display both the inhibitor and the enzyme
you will need to uncheck the Display Selected Only option).
Display atoms within a certain distance of the inhibitor to reveal the key interacting side chains.
Use the measurement functions to give you information about the proximity of the key amino acid
sidechains close to the inhibitor. Does the relative orientation of any of the sidechains to the inhibitor
give you extra information about the nature of the interactions (think about π-π interactions for
example)?
Now show Aricept as a CPK model.
Generate 1 or 2 views which you save as .gif files around the structure which highlight the π-π, π-cation
and h-bonded interactions.
Acknowledgement
Selected Jmol tutorial material was obtained from http://www.bioinformatics.org/jmoltutorials/jtat/_docs/tutuse.htm
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