Wednesday, December 9, 2009

More large RNA's in the horizon.

Nature 462, 656-659, 2009.
From Ronald Breaker's lab at Yale.

In a recent visit of Dr. Anna Pyle (from Yale) to Rutgers I informally asked about the possible existence of new large RNA structures. She definitely was well informed of new studies which show evidence for this, and I was a bit puzzled why I hadn't come across them. Now my guess is that this is because she knew of Breaker's lab results before publication, actually, perhaps she mentioned that there was going to be such a publication coming out..., my feeble memory!.
Our studies are completely dependent on large structural datasets for developing structure-knowledge based statistical models. I am very happily surprised to see evidence for the existence of such data so soon.

One post-doc at our lab who knows that I'm interested in RNA pointed out a paper of possible interest in Nature. Initially I thought that the paper would be related to some other area of RNA research of perhaps immediate medical relevance which I wouldn't be directly interested in from the structural point of view, well... I was clearly wrong.

The paper says that using sequence covariation they have found large ncRNA's in BACTERIA. This came as a surprise since I was believing the statement by Sebastian Doniach in Physics Today November issue, stating that only 1% of DNA in bacteria is non-coding. It seems from what I understand of the Nature article, that there is more than 1% of this DNA that makes up "exceptionally structured noncoding RNA's".
It's also important to note that what they call large ncRNA's are RNA's with a content greater than a 100 bases.

Wednesday, December 2, 2009

Chemical Graph Theory

Volume 51 of the Advances in Quantum Chemistry has an interesting chapter by Ivan Gutman (From Kragujevac University in Serbia) about the influence of Mathematical Chemistry in Mathematics.
He argues that the cases of:

1) Graph Energy.
2) Connectivity (Randic) Index.
3) Graph Spectral Theory from HMO Theory. -- hard to tell --
4) Wiener Index and Graph Distance.
5) Kekule Structures.

Can all be connected in one way or the other to mathematical developments, and in some cases, precede them.

I guess the most puzzling and interesting conclusion that can be drawn from this 2006 article is that chemistry based on graphs and graph theory mathematics can arrive at the same conclusions using quite different frameworks of thought. I believe the same could be argued for areas of Physics and Biology, and therefore this is yet another positive justification for highly interdisciplinary work in the exact physical and natural sciences and a weak argument against absolute rationalism.

Tuesday, November 3, 2009

Again RNA gets the Nobel Prize!

For a beginner it takes time to put into perspective the history of scientific interest in RNA.

Here are some landmarks on RNA Structure:

-- 1956 Alex Rich and David Davies -- Double Stranded RNA **JACS
-- 1956 Mahlon Hoagland and Paul Zamecnik -- tRNA (then called sRNA - soluble RNA) **J. Biol. Chem.
-- 1965 Robert W. Holley -- yeast tRNAala sequenced and secondary structure proposed. **SCIENCE
-- 1968 Nobel Medicine -- Robert W. Holley, Har Gobind Khorana, Marshall W. Nirenberg
-- 1974 Rich's (**Science) and Klug's (**Nature) Groups yeast tRNAphe x-ray structure at 3.0 Angstrom.
-- 1989 Nobel Chemistry -- Sidney Altman and Tom Cech -- Ribozymes
-- 1994 Pley, McKay -- Hammerhead RNA
-- 1996 J. Cate et al. -- P4-P6 Group I Intron.
-- 2000 Various groups publish rRNA x-ray structure.
-- 2006 Nobel Medicine -- Craig Mello and Andrew Fire -- RNAi
-- 2006 Nobel Chemistry -- Roger Kornberg -- RNAPol
-- 2008 Pyle et al. -- Group II Intron.
-- 2009 Nobel Chemistry -- Venkatraman Ramakrishnan, Thomas A. Steitz, Ada E. Yonath -- rRNA

Monday, September 21, 2009

The first peptide bond. EF-P and Ratcheting

In the third week of August Steitz and collaborators at Yale publish in science the crystallographic structures of the T. Thermophilus ribosome with Elongation Factor P (EF-P) bound to it. Also initiator tRNA and mRNA are included in the crystal.
"The essential role of EF-P in the cell may be to correctly position the fMet-tRNAifMet in the P site for the first step of peptide bond formation by making several interactions with the backbone of the tRNA."

Science 325, 909-1032, 2009

An article in the same volume of Science by Cate et al. at Berkeley, shows the crystallographic results of catching the ribosome of e. coli in intermediate states of ratcheting which "provide insight into how tRNAs move into the hybrid state of binding that precedes the final steps of mRNA and tRNA translocation."
"Positioning of tRNA on the ribosome is proposed to occur through a ratcheting mechanism. Central to this mechanism is a rotation of the small ribosomal subunit relative to the large subunit (see Figure) that occurs in all stages of translation—initiation, elongation, termination, and ribosome recycling"

Science 325, 1014-1017, 2009

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Thursday, September 10, 2009

Yet another interesting RNA (anti-NF-(kappa)B RNA aptamer)

Whereas in DNA you have a quite small set of possible structures, ranging from A-form to Z-form, in RNA there's a whole ZOO of possibilities. The one I ran upon this week has a difficult name:
anti-NF-(kappa)B RNA aptamer
The whole idea of what this aptamer seems to be doing is to mimic the B-form of DNA, which RNA rarely manages to attain. Of course, this so called mimicry is obtained in the backbone, which, of course, determined the width of the grooves, which are the most common mechanism which nucleic acids use for their recognition of other molecules inside the cell.
It's quite interesting how three guanines stack in top of each other, two are from the same side of the strand, and one is from the opposite side of the strand, as can easily be seen in the following figure.

The work was carried out by Nicholas J. Reiter, James Maher III, and Samuel E. Butcher at Wisconsin, published in NAR, 36, 1227-1236, 2008

Friday, August 14, 2009

What is an RNA Genome?

The idea of an RNA genome is, for now, taken in the context of retroviruses like HIV.
Joseph Watts and Kevin Weeks at UNC (Chapel-Hill), have used a technique called SHAPE (selective 2' hydroxyl acylation analyzed by primer extension), to determine conformational "flexibilities" of nucleotides, and extrapolate their results to secondary structure prediction of the RNA (9173 nucleotides) in HIV. Their results can be found at: DOI. The marketing title of their results is "Architecture and secondary structure of an entire HIV-1 genome".
It seems like these flexibilities are just a determination of whether there is base-pairing or not.

Monday, July 27, 2009

The importance of miRNA

miRNA's, as stated in the latest issue of Nature (460, 466-467 (23 July 2009)) bind in a "sequence-specific manner" to mRNA. Suzuki and Miyazono

Here's where structural knowledge based models of canonical and non-canonical RNA base-pairs and base-pair steps are fundamental. There is practically no knowledge of what miRNA sequence dependence means in terms of three dimensional structure of RNA.
How do miRNA's bend (or deform) depending on canonical and non-canonical sequence?
What role do stacking interactions play in miRNA binding?

It is amazing to see that even though miRNA's were introduced more or less recently into the body of knowledge of cell biology, that is, around 2001 when 3 papers about them were published in science (http://www.sciencemag.org/cgi/content/summary/294/5543/797), when reading nowadays literature they seem to be standard knowledge and present in every other aspect or regulatory mechanisms.

Reminder:
To make mature miRNA's they follow this path:
pri-miRNA --> DROSHA --> pre-miRNA --> DICER --> miRNA

Wednesday, July 1, 2009

Corey D.R., the son of Elias James Corey

Double stranded RNA can interfere gene expression as was shown by Andrew Fire and Craig Mello in 1998.
If Corey is right, gene expression interference would not only happen at the translational level by targeting mRNA's, but it could also happen at the transcriptional level, by interaction of what he calls agRNA's (anti-gene RNA) with DNA promoter regions.
He makes a good case in his article called:

"The Puzzle of RNAs that Target Gene Promoters"
ChemBioChem 2009, 10, 1135 – 1139


I, of course, would like to know the structures of this RNA's.
What is their non-canonical base-pair content?
Are they hairpins?
What difference would it make for gene promoter targeting if the RNA's are dumbell RNA's?

Friday, June 5, 2009

Ribozyme Ligase

According to Michael P. Robertson and William P. Scott from U.C. Santa Cruz as published in SCIENCE (2007), 315, 1549 - 1553.

Life originated, according to the RNA World hypothesis, from self-replicating ribozymes that catalyzed ligation of RNA fragments. We have solved the 2.6 angstrom crystal structure of a ligase ribozyme that catalyzes regiospecific formation of a 5` to 3` phosphodiester bond between the 5`-triphosphate and the 3`-hydroxyl termini of two RNA fragments.

PDBID: 2OIU
http://www.pdb.org/pdb/explore/explore.do?structureId=2OIU

Tuesday, May 12, 2009

Jesse Stombaugh, Craig L. Zirbel, Eric Westhof and Neocles Leontis, NAR, 2009, 37, 2294-2312

A technical question remains as to the ability of FR3D to go past rnaview in identification of base-pairs using the Leontis-Westhof annotation. That is, is it the case now that no N.A. base-pairs appear in the FR3D output?
A command line interface instead as an option to the Windows GUI, would be very useful for researchers doing large scale classifications.