Noel O'Blog

Wednesday, 12 December 2007

Using Jmol for Drug Design - Depict Ligand in Active Site

In the previous article, I showed how to install Jmol. This article will look at depicting a ligand in a protein active site with a few extra complications. This example was not chosen to showcase Jmol - this is a real-life example of a figure I need to create. You can find on the web lots of examples of scripting Jmol to turn on/off ball-and-stick models. Figuring out how to do difficult things is a bit harder, and I hope others will find this example useful...

Specifically, I want to depict the ligand in the protein active site, with the protein represented by an isosurface coloured by depth in the protein (values which I will supply), and with protein-ligand hydrogen bonds shown. I have a protein .MOL2 file with hydrogens added; I have a ligand .MOL file, I have the corresponding protein .PDB file (no hydrogens and the ligand and waters have been removed); and I have a text file containing, for each atom in the protein .MOL2 file, a value related to the depth of that atom in the protein. And here is the final image (screenshotted from the browser , cropped a little, and saved as a JPG with zero compression - click for the original image):

Before presenting the necessary code, to help understanding I note that Jmol imposes some constraints:

bonds can only exist between molecules in the same model
if the slab is turned on, it cuts through every model
Jmol can identify the residue names in the PDB file, but not in the .MOL2 file
Jmol does not automatically identify protein-ligand hydrogen bonds
if mapping property data onto an isosurface, it needs to be supplied for every atom in the model (actually, there is an alternative, but this is a good rule of thumb)

I should also point out that Jmol can colour isosurfaces by depth in the protein automatically, but I wanted to use my own measure of depth. Update 13/12/07: Due to popular demand, here is the actual applet in motion: [low quality] [high quality]. And finally, after all that, here is the code (available also as a download):

<html>
<head>
  <script type="text/javascript" 
  src="file:///D:/Tools/Jmol/jmol-11.3.53/Jmol.js">
  </script>
  </head>
<body>
<script type="text/javascript">
  var protein = "1p62";
  jmolInitialize("file:///D:/Tools/Jmol/jmol-11.3.53", true);
  var jmolcmds = [
  // Load the molecules
  "load file:///D:/Ligands/" + protein + "_ligand.mol",
  "set appendNew = false",
  "load APPEND file:///D:/Proteins/" + protein + "_protein.mol2",
  "set appendNew = true",
  "load APPEND file:///D:/Proteins/" + protein + ".pdb",

  // Turn up display quality but don't yet show anything
  "display none; set antialiasDisplay true",

  // The following is the output of "show orientation"
  "reset;center {67.99645 35.5767 19.92025}",
  "rotate z -21.47; rotate y 25.81; rotate z 74.65",
  "zoom 400.0; set rotationRadius 35.03",

  // Add the HBonds
  "model 1.1",
  "connect 3.1 (molecule=1 and elemno=8) \
(molecule!=1 and elemno=7) HBOND RADIUS 0.07 CREATE",
  "connect 3.2 (molecule=1 and elemno=7) \
          (molecule!=1 and elemno=8) HBOND RADIUS 0.07 CREATE",
  "connect 3.1 (molecule=1 and elemno=8) \
(molecule!=1 and elemno=8) HBOND RADIUS 0.07 CREATE",
  "connect 3.1 (molecule=1 and elemno=7) \
(molecule!=1 and elemno=7) HBOND RADIUS 0.07 CREATE",

  // Load info for isosurface and draw it
  "{model=1.1}.property_d = load(\"D:/Data/" + protein +"_rd.txt\")",
  "isosurface select(molecule!=1 and within(10.0, molecule=1)) \
ignore(molecule=1) resolution 5 sasurface 0 \
COLOR ABSOLUTE 30 120 REVERSECOLOR MAP property_d",

  // Select and label the HBonded protein atoms in model 2.1
  "define hbondedproteinatoms within(3.2, true, \
model=1.1 and molecule=1 and (elemno=7 or elemno=8)) \
and not within(0.1, true, model=1.1 and molecule=1) \
and model=2.1 and not elemno=1 and not solvent",
  "select hbondedproteinatoms; font label 15 SANSERIF BOLD",
  "set labelFront; color label white; label %n%R",

  // Add to selection the ligand and
  // its HBonded protein atoms in model 1.1
  "select selected or (((molecule=1 and model=1.1) or \
within(3.2, molecule=1 and model=1.1 and \
(elemno=7 or elemno=8))) and not elemno=1)",

  // Slice through everything with a slab
  "slab on; slab 51",

  // Remove the Jmol logo (I will reference Jmol instead)
  "set frank off",

  // Show the selected data from all models
  "model 0; display selected",
  ];
  jmolApplet(700, jmolcmds.join("; "));
</script>
</body>
</html>

Tuesday, 11 December 2007

Using Jmol for Drug Design - Installation

Jmol is well known as the program for showing 3D structures in webpages. It's free, it's open source and it has excellent support. However, I've often felt that Jmol's potential is not being fully realised by chemists in general, and by me in particular. So this series of posts will describe how to use Jmol to create publication quality pictures of drug molecules in a protein active site. More about that in the next post; first we have to install Jmol.

I'm going to be running Jmol as an applet in Firefox on my Win XP machine. Note that Jmol also comes as a stand-alone application. The benefit in running Jmol in a web browser is that you have access to the JavaScript scripting language. The only downside is that you need to remember to use the signed applet (as described below) or else you will have problems opening files at arbitary locations on your computer.

Step one is to download the absolutely latest Jmol. If you look at the download page, see under Jmol Prerelease Tests for the cutting edge (currently 11.3.54). There's a new version practically every day. The file you want is called something like jmol-11.3.54-binary.zip. Download and unzip the file into something like D:\Tools\Jmol\jmol-11.3.54.

Next, download the protein structure 1hnn from the PDB and save as something like D:\Proteins\1hnn.pdb.

Now we can create the "Hello World" of Jmol applets, which simply loads and displays the protein structure you have just downloaded. Save the following code as something like D:\Applet\HelloWorld.htm. You should change the paths in the following HTML to correspond to the actual paths on your computer:

<html>
<head>
<script type="text/javascript"
        src="file:///D:/Tools/Jmol/jmol-11.3.54/Jmol.js">
</script>
</head>
<body>
<script type="text/javascript">
jmolInitialize("file:///D:/Tools/Jmol/jmol-11.3.54", true);
var jmolcmds = [
  "load file:///D:/Proteins/1hnn.pdb",
  ]; 
jmolApplet(700, jmolcmds.join("; "));
</script>
</body>
</html>

Open the HTML file with Firefox. The first time you do this, you will be asked whether you trust Jmol to access your hard drive responsibly. You should say yes to this if you wish to proceed. This warning indicates that you are using the signed applet rather than the unsigned applet. Using the signed applet on a live website will probably discourage users, so is best avoided, but it is very useful when running locally on your machine, as the unsigned applet is restricted to opening files in particular directories.

The next post takes Jmol to the next level, uh, level 2.

Wednesday, 5 December 2007

Python gives you wings

Along with Piled Higher and Deeper, I really like xkcd. Today's comic is on a theme close to my heart:

To pander to the readership of this blog, here's one on a more popular scripting language:

Tuesday, 13 November 2007

Using R from Python - the best of both worlds

R is a programming environment containing every known statistical method; however, it's ugly and difficult to program in. Python has only a small number of statistical methods (which are available through SciPy), but it's elegant and easy to program in. Both have graphing libraries which leave a lot to be desired in terms of ease of use, but the graphs from Python's matplotlib are a lot more polished. So, I'd like to use R from Python...

In order to do this, you will need to install the RPy library (as well as Python and R, of course). I'm working on Windows, but I've used this previously on Linux. As an example, here are three ways to access the same hclust object from Python. They each illustrate different aspects of the Python/R interface:

from rpy import *

# START OF METHOD 1
hclust = r("""
    a <- read.table("cpOfSimMatrix.txt")
    mydist <- dist(1-a)
    hclust(mydist)
""")
r("rm(a)") # Ends with an error if you leave anything in memory
# END OF METHOD 1

# START OF METHOD 2
set_default_mode(NO_CONVERSION)
a = r.read_table("cpOfSimMatrix.txt")
mydist = r.dist(r["-"](1,a)) # Note the trick for '1-a' here
set_default_mode(BASIC_CONVERSION)
hclust = r.hclust(mydist) # Converts R object to Python dict
# END OF METHOD 2

# START OF METHOD 3 (here's one I created earlier)
r.load(".RData")
hclust = r('myHclust')
# END OF METHOD 3

For further examples, check out Peter Cock's excellent pages on combining R and Python.

Thursday, 8 November 2007

Take a molecule for a spin with Avogadro

Avogadro 0.2 is an early stage release of a new open source molecular viewer and editor. It's available for Windows, Linux and MacOSX, so there's no excuse not to try it. I took it for a test drive for the first time a week or so ago (this was on Windows), and was very impressed. Sure, there are some rough edges, as you might expect with such a low version number, but it's already capable of matching the existing competition and is sure to become the molecular editor of choice with the next release.

Once it starts, open up a molecular structure file (for example, a PDB entry) and immediately choose the navigation tool (next to the Pencil in the Tools toolbar). The left mouse button rotates the molecule, the middle zooms, and the right translates. So far, so Rasmol.

However, it's the attention to detail in the user interface that makes Avogadro stand out from the crowd. If the initial click to rotate is on an atom, the molecule rotates around the atom, whereas otherwise the molecule rotates around its centroid. Something else you will notice is the eye-candy, which really aids clarity. When rotating, a set of curvy arrows indicate the degree of rotation. If you choose the Bond Centric Manipulation Tool (indicated by an icon containing the number 90) and click on a bond, you will see bond angles lovingly displayed as semi-transparent segments. Then if you click and drag on an atom adjacent to the bond, the visualisation of the dihedral angles as you alter them is pretty cool (see below).

So what else has Avogadro got? I didn't try the molecular builder, the force-field optimisation nor the export to POV-Ray, but they're all there. I'm more interested in what's to come. Avogadro uses a plugin architecture, which means that it will be easy to incorporate third-party add-ons. Along with forthcoming support for scripting languages, this will allow me to incorporate elements of cclib or GaussSum into Avogadro.

But that's all in the future. For now, I'm just wondering how many times I can rotate this dihedral angle until it falls off...

Wednesday, 7 November 2007

Preventing Spam on Mediawiki at SourceForge

Mail spam is annoying. But spam on a wiki is even more annoying. If you've spent your free time writing documentation, there's no way you want to see junk text or link spam inserted into the middle of your flowing prose. In an earlier article, I described how to install a Mediawiki wiki on SourceForge. After a while you will start to get your first spam. And so the battle begins...

Wikis don't look very impressive as a website, but for an open source project they are a great way of maintaining documentation. Nobody likes writing documentation, which is why it needs to be made as easy as possible. For example, if a user mails the project mailing list with a question about installing that software, it usually means that the documentation needs to be updated and this can be done in about a minute. (On the other hand, if a project has a frequently-asked questions page, it means that they couldn't be bothered improving the documentation.)

Fortunately, spam can simply be controlled using permissions (thanks to David Wild for some of these suggestions). To begin with, make sure you keep an eye on the Recent Changes feed on your wiki (use an RSS reader). (As an aside, if your Recent Changes feed is broken, a possible cause is that you have installed an extension and included a rouge blank line after the final "?>" - this happened to me.)

Next you need to edit the permissions in LocalSettings.php to disable anonymous edits and disable account creation except by users who already have accounts. Of course, the admin is always allowed to do whatever. I'll explain the rationale for this below, but first here are the settings:

# No anonymous editing allowed
$wgGroupPermissions['*']['edit'] = false;
$wgGroupPermissions['user']['edit'] = true;
$wgGroupPermissions['sysop']['edit'] = true;
# Only users with accounts can create accounts
$wgGroupPermissions['*']['createaccount'] = false;
$wgGroupPermissions['user']['createaccount'] = true;
$wgGroupPermissions['sysop']['createaccount'] = true

On one of the wikis I am involved with on SourceForge, we had already disabled anonymous edits. However, anyone could create an account. At some point the spammers upgraded their spam software and were then able to create accounts on the wiki. Since the RSS feed for recent changes was not working (for the reason described above), it was three days and about 1000 spam accounts later before I realised the problem. At that stage it was too late to implement the solution I described above. Instead, I created a new group 'human', added the 10 or so real accounts to that group and gave them permissions while simultaneously removing all permissions from the regular 'user' account.

# Only 'humans' can edit
$wgGroupPermissions['*']['edit'] = false;
$wgGroupPermissions['user']['edit'] = false;
$wgGroupPermissions['human']['edit'] = true;
$wgGroupPermissions['sysop']['edit'] = true;
# Only 'humans' can create accounts
$wgGroupPermissions['*']['createaccount'] = false;
$wgGroupPermissions['user']['createaccount'] = false;
$wgGroupPermissions['human']['createaccount'] = true;
$wgGroupPermissions['sysop']['createaccount'] = true;

Bye-bye spam. Of course, I still had to revert about 30 edits...:-/

Image credit: Spam wall by freezelight

Friday, 2 November 2007

ANN: cclib 0.8 released - parsers and algorithms for comp chem

On behalf of the cclib development team, I am pleased to announce that cclib 0.8 is now available for download.

cclib is an open source library, written in Python, for parsing and interpreting the results of computational chemistry packages. It currently parses output files from ADF, GAMESS (US), GAMESS-UK, Gaussian, Jaguar, Molpro and PC GAMESS. A paper is currently in press.

The main changes in this release are:
* the addition of a Molpro parser
* support for writing data to/from files as JSON
* API additions: charge, multiplicity, Natural Orbital coefficients
* New method: Lowdin population analysis
* use of Numpy instead of Numeric

Among other data, cclib extracts:
* coordinates and energies
* information about geometry optimization
* atomic orbital information
* molecular orbital information
* information on vibrational modes
* the results of a TD-DFT calculation

cclib also provides some calculation methods for interpreting the electronic properties of molecules using analyses such as:
* Mulliken and Lowdin population analyses
* Overlap population analysis
* Calculation of Mayer's bond orders.

For more information see our website, read the tutorial, or send us an email.