JavaScript Menu, DHTML Menu Powered By Milonic

Molecular Modeling Practical

This tutorial provides a short introduction to the set-up and running of Molecular Dynamics (MD) simulations of small peptides. The protocol used is a suitable starting point for investigation of peptides, provided that the system does not contain non-standard groups. At the end of the tutorial, the student should know the steps involved in setting up and running a simulation, including some reflection on the choices made at different stages. Besides, the student should know how to perform quality assurance checks on the simulation results and have a feel for methods of analysis to retrieve information.

Tryptophan cage

The Tryptophan cage is a short peptide sequence designed to study the folding of proteins.

The seminal Trp-cage was designed in 2002, see Neidigh et al., and is a 20 amino acid peptide. The structure has been solved by NMR and by X-ray crystallography and is characterized by a central tryptophan residue stabilized by hydrophobic interactions with three consecutive proline residues on a loop adjacent to a short alpha-helix on which the Trp-residue is central. The adjacent moieties are connected by a 3-10 helix, and further stabilization is provided by a salt-bridge.

In this tutorial, you are going to set-up and run a short simulation of a Trp-cage and investigate some of its structure and dynamics. Extensive modeling has been performed by others and comparisons have been made to experimental observations concerning the structural dynamics and folding process. It is well beyond the scope of this tutorial to attempt such comparisons ourselves but it makes interesting reading of a fundamental process of life! See, e.g. Scian et al. These papers are also available from the NESTOR site.

Starting structures

Before anything else, starting structures have to be obtained. These can be retrieved from the Protein Databank, which is a repository for three dimensional structures of proteins. To start the tutorial, download a structure for the Tryptophan cage from the database. The best choice may be the structure determined by Neidigh et al., 1L2Y.

Write down the PDB-identifyer for your Trp-cage structure.

Make sure that you rename your pdb-file protein.pdb and that it is located in the directory where you want to do your calculations. You can achieve this through the graphical interface dragging or copying your file to the target directory, or by using the Linux command 'cp' (instead of 'whatever-you-named-your-file' you should probably need to type ~/Downloads/1l2y.pdb; in any case, the text should point to the place your PDB file of the Trp-cage is located):

cp 'whatever-you-named-your-file' protein.pdb

Visualization

Now first have a look at the structure in a molecular viewer. The following instructions are for VMD (Visual Molecular Dynamics).

vmd protein.pdb

This opens a window showing the representation of the PDB structure and a main menu window. You can scroll through the deposited NMR structures by clicking on the bar at the bottom of the main menu. More detailed analysis will follow later. Exit VMD via the main menu.

Next, have a look at the file by opening it in an editor. First make sure that you name your pdb-structure protein.pdb, so all commands presented here work according to plan. Linux has many editors, but a convenient one with a graphical interface is 'gedit'.

gedit protein.pdb

The PDB file contains a lot of information regarding the peptide, the experimental methods used, conditions, etc. It also contains a listing of each atom with the Cartesian coordinates. Note that there is no information in the file regarding bonding, whereas VMD, as most molecular viewers do, did draw bonds between atoms. These bonds were inferred from the interatomic distances. Close the application 'gedit'. This frees up your command line in the terminal window, so that you can enter new commands.

Now that you have a structure file, a Molecular Dynamics Simulation can be set-up. This is the next stage in the tutorial, and can be found here .