Sunday, October 07, 2007

Molecular Beauty

My genetics students have a little assignment. I have been slowly introducing them to some of the major bioinformatics tools available through the National Center for Biotechnology Information.

The idea is to get their feet wet so that they can go further on their own and not be too intimidated by reams of forbidding looking database records.

So far they have looked at OMIM and BLAST. This weekend their task is to load NCBI's Cn3D protein and nucleotide molecular viewer. The next step is for them to find certain important molecules related to genetics so we can make a molecular gallery for the class.

The Cn3Dprogram allows researchers to see and manipulate nucleic acid and protein structures in various ways. Since we have just finished the basics of DNA replication, and are getting ready to do protein synthesis and the regulation of gene expression, I hope that looking at some of the major actors in these processes will help the students become more comfortable with these molecules, more so than looking at a flat amino acid or nucleotide sequence.

Beauty is at all levels of organization; the balance of order and spontaneity that I think makes for beauty, is evident even at the molecular level. So I thought show a few examples beyond the iconic DNA double helix.

My first example, shown in the picture above is a protein that serves as a transcription factor. The proteins polypeptide chains appear pale blue. and it is bound to a DNA molecule shown in the dark blue and brown helical strands on the right. The structure is from a paper by Beth A. Chaney, Kimber Clark-Baldwin, Vrushank Dave, Jun Ma, and Mark Rance
Biochemistry, 2005, 44, (20), pp 7497–7511.

If you want to see and manipulate this and other structures I mention, download the Cn3D viewer, follow the instructions and then go to this structure summary link.

This particular transcription factor binds to a small region of DNA called a homeobox. Homeoboxes are important in the patterning of development. The transcription factor called Pituitary homeobox protein is critical for proper development of the anterior portion of the eye. Mutations in the gene coding for the transcription factor often lead to a syndrome called Rieger syndrome (OMIM = 601542).

Here is a different rendering also rotated a bit, showing a space filling model of the homeobox protein bound to the DNA. The DNA double helix is shown in blue and brown, the homeobox protein is in pink.

One of the nice things you can do with the viewer is highlight different parts of the molecule that might be involved in a binding site with your mouse. The part you select is also highlighted in the sequence data window. This is very useful for activities ranging from drug design to studying protein evolution.

So you can see how this works, here is a screen shot showing a particular amino acid in the protein and a guanine to which it binds in the DNA.

But I stray from my main theme, and that is beauty at the molecular level. Maybe a transcription factor has a beauty only a molecular geneticist can love, but what follows are several beautiful molecular structures, rendered using the viewer along with their structure summary links for those who want to examine them in different ways using the viewer.

A Nucleosome.

Nucleosomes are the basic structural unit of chromosomes in eukaryotic cells, such as the cells in your body. Nucleosomes consist of a core of proteins called histones around which wrap a two coils of DNA. Can you pick out the DNA?

Structure summary.

A DNA mimic.

Gyrases are enzymes that manipulate the coiling of DNA during DNA replication. These are the sorts of enzymes one might which to have when trying to detangle fishing lines or kite strings. Unfortunately Gyrases only work on DNA. In searching for gyrases, I found this wonderful protein which turned out not to be a gyrase but rather a protein called a The Pentapeptide Repeat Protein. It is from the bacterium which causes tuberculosis. These sorts of proteins are wide spread in bacteria and their usual function is not known. But in the tuberculosis organism this protein confers resistance to a class of antibiotics called Fluoroquinolones. I also inhibits the activity of gyrases. It can do this because the pentapeptide repeats (brown) mimic the geometry and charge properties of DNA.

I show two angles so you can see better just how neat this molecule is!

Structure summary.

Sliding clamp protein.

Clamp proteins hold DNA in place, for example during DNA replication and clamp proteins seem to often have really interesting structures as in my example.

A different rendering
of the same clamp shows that each of the rings is made from three polypeptides. So think of the clamp as a machine with six large molecules for parts!

So I hope you can see some of the beauty
I see in these structures. Lest anyone try imbuing these structures with metaphysical freight, to me the real beauty is that even within the confines of the cell evolution has produced adaptations at the nano scale every bit as wonderful as the large scale adaptations of organisms to their environments.

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