Molecular Design and Dynamics

Molecular Design and Dynamics

Molecular Design and Dynamics


·        To develop skills using VMD to investigate protein and peptide structures.



Throughout these instructions you will find a series of activities to perform or questions to answer. These will be outlined with boxes throughout the text. Your results/answers should be collected together in a Word documentas you proceed through the exercise.  This tute will be conducted across weeks 6 and 7.


All the files you need for the Exercise can be found on Canvas. We recommend you download these to the desktop before you start.


Part 1. Visualisation and Interpretation of Protein Structures

VMD is a molecular visualization program for displaying, animating, and analyzing large biomolecular systems using 3D graphics and built-in scripting. In this exercise you will learn how to use VMD to investigate protein structures.


RestartPlaySpeed SliderStart by opening the program VMD. You should find this on MyDesktop. Several windows will open. The important ones are the VMD Display window and the VMD Main window:













Figure 1. VMD Display,Mainand Graphical Representations windows.

In the VMD Main window click File>New Molecule…

Browse for the file 2Q8K.pdb. Click Open then Load. This file contains a protein structure of PA2G4. You may want to look at the details of this protein in the Protein Data Bank.

View the proteinin the Display window. Use your mouse to rotate the peptide.

In this view it’s a bit difficult to make any sense of the structure, however VMD has tools to help.

Open the Graphical Representations window. (Graphics>Representations…)

Changing the Colouring Method and Drawing Method can help bring out important features of the peptide.  Explore the options available (some options require further data and will not currently show anything).

Overall Protein Shape

To view the overall shape of the protein, change the Drawing Method toQuickSurf. Rotate the protein to give a good view of the structure

2.1 Take a screenshot of the overall shape of the protein and include this in your report.2 marks


Exploring Secondary Structure

To get the best view of the secondary structure of the peptide, chooseColoring Method: Secondary Structure and Drawing Method: NewCartoon.

Colour key:


Alpha helix



Beta sheet



Beta turn






2.2Describe the structure of PA2G4 in terms of the numbers and types of the various secondary structure elements present and the way these are arranged to give the tertiary structure. Illustrate this with screenshots.21 marks


Now change the Coloring Methodto Charge orElement

2.3 Describe the distribution of the different residue types throughout the protein. Illustrate with screenshots. What are the implications of this distribution for the folding of the protein and its solubility in the cytoplasm of cells? 9 marks


Residue-Residue Interactions

You can also view particular residues of the protein that you are interested in.

Change the Drawing Method to CPKand the Coloring Methodto Name.

In the middle of the Graphical Representations window there is a field titled Selected Atoms. This should currently say “all”. Change this field to say “resid40” and hit “Enter” on your keyboard.Now only residue number40in the amino acid sequence will be displayed.

If you want to re-centre the view on the selected residues, click in the Display window and hit “=” on the keyboard. Remember this – you will use it a lot!

To find out what kind of residue it is, hit the “1” key on your keyboard. This starts “labelling mode”. Whenever you click on an atom a line of green text will come up telling you information about the residue and atom selected. Click on the blue nitrogen atom of residue 40. The text should say: SER40:N. This means that the residue is a serine amino acid (SER), it is at position 40 in the sequence and the atom selected is the backbone nitrogen atom (N). To remove the label, click again on the nitrogen atom.(Note: You only need to hit “1” once, then you can label as many atoms as you want.)

Now change the Selected Atoms field to “resid155360”. This will show both residues 155 and 360. You can now examine the interactions between them.

There are three different types of interactions that you will need to look for in this exercise: covalent interactions (peptide bonds anddisulfide bonds), hydrogen bonds (interactions between NH or OH hydrogens and N or O atoms), and hydrophobic interactions (between aliphatic hydrogens).

2.4Examine the interactions between each of the pairs of residues in the following table. Some pairs may have more than one interaction type. Fill in the following table and include screenshots of these interactions in your report: 24 marks

Residue 1

Residue 2

Interaction Type(s)










Hydrogen Bond






















Note: To measure the distance (in Ångstrom, 1 Å = 10-10 m) between two atoms hit “2” on the keyboard to enter measuring mode, then click on each of the atoms. In very close-up views it can be tricky to hit the right spot to select the atom. Whenever you successfully select an atom the atom label will appear or, if the atom had been selected previously, disappear.

If you’re getting too many labels on the screen, you can get rid of these by going back to the VMD Main window and open the Labels… window (Graphics > Labels…). You can then highlight the atom label(s) you want to delete and hit the Delete button. To delete labels of interatomic distances, click the down arrow next to the box at the top left which says Atoms and change it to Bonds. You can then highlight and delete the “bonds” you have labelled.

Look at residue 55

2.5 What is different about this residue compared to the others you have looked at? Why is it different? 6 marks

Look at residues 281-286

2.6 What different about these residues? Why are they different?5 marks


Part 2Molecular Dynamics Simulations

Molecular dynamics is a computational method used to simulate the physical movements of the atoms and molecules in a system over time. In molecular dynamics simulations of biomolecules, the system of interest (in our case a-conotoxin Vc1.1) is placed in a box of water molecules and the temperature and pressure is held constant (usually at room temperature and pressure) during the simulation. This is designed to show how the protein would behave under physiological conditions. We are going to view the results of two different simulations of this conotoxin. One is a standard protein, one a chemically reduced version.The initial position of both is the Xray structure which is usefulfor comparison.

In the VMD Main window click File>New Molecule… Browse for the file: conotoxin.pdband Load it.

Start by looking at how the backbone of the protein moves during the simulation. Change Selected Atoms back to “all”, Coloring Methodto Secondary Structure and Drawing MethodtoNewCartoon.

Now click the Play button in the bottom right-hand corner of the VMD Main window to start viewing the simulation.

Click the Play button again when you want to stop the simulation.

2.7Examine the molecular dynamics simulation results for the conotoxin. How flexible is the backbone of the peptide? Do you see major changes in the backbone structure during the simulation or only minor vibrations? How does it compare to the initial X-ray structure?4 marks

To look at the behaviour of the amino acid side chains during the simulations, change the Coloring MethodtoName and the Drawing MethodtoCPK the start the simulation running again.

If the simulation is going too fast to look at the side chain motions, just shift the speed slider to slow it down.

2.8You should notice that the side chain of one amino acid shows a lot more movement than the others. What is the name and number of this amino acid? What kind of interaction does the side chain of this residue make with its partner? What does theflexibility of this side chain in the simulationtell you about the strength of this interaction?9 marks

Change theDrawing Methodbackto NewCartoon.

Disulfide bonds are an important structural element in proteins.

2.9 Why are disulphide bonds particularly important in conotoxins?

In the VMD Main window click File>New Molecule… Browse for the file: conotoxin-red.pdband Load it. Change theColoring MethodtoColorID and the Drawing MethodtoNewCartoon.

To line up the atoms of the two structures, bring up the VMD Main window and choose Extensions > Analysis > RMSD Trajectory Toolthen click ALIGN.

Find a good orientation to view the structures then click the Play button to view both simulations at the same time. Make sure you view the full simulation – the most interesting behaviour comes towards the end.

3.0 Compare the flexibility of the peptide backbone for the oxidised and reduced forms of the a-conotoxin. How do these differ? Based on these simulations, how important are the disulfide bonds for maintaining the a-conotoxin structure?7 marks

4 marks to be given for Scientific English, figure legends, references etc.

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