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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.

Introduction and Outline

The aim of this tutorial is to get insight into the capabilities of modern-day Molecular Dynamics software and the type of data that can be obtained from a Molecular Dynamics simulation of a small peptide. At the end of the tutorial the student should be able to:

  • Set up and run Molecular Dynamics Simulations of proteins using Gromacs
  • Perform quality assurance checks and analysis on simulation results
  • Compare simulation results obtained from different simulations
  • Set up and run an MD simulation including distance restraints deposited in the Protein Data Bank

Although a report is not required, it is useful to take notes reflecting on the purpose of the work and the results obtained. Specific questions are given in the tutorial, which are meant to guide the student's thinking. A description of the report, what it should contain and which questions are to be answered, is given on the report page. In the text, questions and assigments are indicated by grey boxes, like the following:

Write down your name and those of the members of your group

For the Structural Biology course (WLB07079) at the University of Groningen, students are required to prepare four files as part of their course work. This assignment is described on a the assignment page.

Commands are given in white on a blue background. These have to be typed carefully, since the shell (the program parsing the commands) is case-sensitive. A common error that may occur is replacing a 0 (digit zero) for an O (capital letter O), an l (lower case letter l) for a 1 (digit one), or vice-versa. You might want to copy-paste the commands, which is as simple as selecting them with the mouse and pressing the middle mouse button on the spot where the command should be entered. If you do this, be aware that sometimes the characters do not copy correctly, in particular the - may give problems! (The - in command lines is used to specify options, for example -o test.xvg specifies that the name of the output file (-o) should be test.xvg).

Although many Linux programs have a similar look and feel to Windows, many scientific programs do not have graphical user interfaces (GUIs), but work from the command line. To work with them, you need to start up a terminal. Find a terminal program on your Linux computer and start it up.

To open a terminal, go to the top left-hand corner of the screen and open the menu. In the menu, you either see the application "Terminal Emulator", or you can look for it by typing terminal in the search box. Start the terminal window application. You are supposed to type the commands in blue in the terminal. Now first try the following commands:

whoami

This lists your current user name. Make sure you're not logged in as "root".

ls -l

This gives a listing of the things that are in the directory where you are. Use this if you encounter errors like "file not found".

pwd

This command shows you the full path of the directory where you are.

Mind that copy-pasting does not relieve you from reading the text! You can't run this tutorial without the instructions around the commands. It is naively assumed that the intention of the person following the tutorial is to learn something. In some cases you might be reminded to read carefully, by a comment like the following:

Read carefully!

Molecular Dynamics

Classical molecular dynamics simulations use Newton's equations of motion to calculate trajectories of particles, starting from a defined configuration. For each particle in the system, the total force acting on it is calculated from the interactions with other particles, as described by the force field. The force divided by the mass of the particle gives the acceleration, which, together with the prior position and velocity, determines what the new position will be after a small time step. The high spatial and temporal resolution make molecular dynamics simulations useful for testing models based on experimental data, for understanding principles underlying the function and to formulate new hypotheses. Unfortunately, system sizes are limited, as are time scales.

Gromacs

This tutorial uses Gromacs (http://www.gromacs.org/) for performing and analysing molecular dynamics simulations. Gromacs is a suite of programs which is freely available under the GNU GPL (General Public License). The programs have a command-line interface, which means that each step involves typing the name of the program and a number of arguments. Note that the commands are case sensitive and each command has to be typed exactly as in the tutorial. More information about Gromacs as well as the manual can be found on the Gromacs web site.

Linux

Since the programs have a command-line interface, there is no escape from using a terminal. Although it is possible to run Gromacs under Windows in a DOS terminal, there are several benefits attached to using Linux, which is the choice for this tutorial. For some students the transfer to Linux from Windows will form an obstacle as they are much used to the interface Windows offers. It is important to note that Linux is not intended to be a free clone of Windows. It is a powerful, highly costumizable operating system, which allows one to get much more performance from a computer. Nevertheless, in many ways Linux can be used as Windows through the graphical interface. Many scientific programs do not have a graphical user interface, but must be operated from the command-line. Gromacs is such a program.

To start using the Linux terminal, it is necessary to know the most basic commands (ls, cd, mkdir, cp, mv, rm, more). Some more information about linux/unix can be found here and here. A reference card (cheat sheet) can be found here .

To open a terminal, go to the top left-hand corner of the screen and open the menu. In the menu, you either see the application "Terminal Emulator", or you can look for it by typing terminal in the search box. Start the terminal window application. You are supposed to type the commands in blue in the terminal.

Preparation

If you are working on the LWP at the university of Groningen, you can have all the commands necessary for these exercises by copying the bash-environment of one of the users. Open a terminal, make sure you are in your own home directory (first command shown below), and copy the bashrc file:

cd

cp /home/p162691/.bashrc .

source .bashrc

You will need to do this only once. Each next time you open a terminal window, or login the system will know where to find the programs.

To get started with the tutorial proper, make a directory where you will perform your simulation. Use a self-explanatory and unique directory name. It is good practice to keep your directories organized, starting with a directory for the project, which in this case could be 'md-tutorial', or 'trp-cage' if the subject is the Tryptophan cage. In that directory, there should be directories for each simulation or for sets of simulations that reflect part of the project.

mkdir md-tutorial

cd md-tutorial

Renaming your protein "protein.pdb" allows simply copy-pasting all commands. This will be shown on the next page. Be sure to read carefully and to check at each step whether it was successful. Read the output! In case a program gives an error message, it is usually self-explanatory. Check file formats and program output to understand the processes at each step. Feel free to ask the assistant(s) for help! Most of the files are readable, except for files ending in .tpr, .xtc, .trr and .edr.

If you feel ready, click here to proceed.