RNA Facts and News

Posting latex equations in blogger.

2012-01-24T02:19:00.000-08:00

When using the mathjax javascript code found at:

http://www.mathjax.org/docs/1.1/start.html#mathjax-cdn

One can post mathematical equations using latex as in the following example:

LaTeX Code:
When a \ne 0, there are two solutions to ax^2 + bx + c = 0 and they are
x = {-b \pm \sqrt{b^2-4ac} \over 2a}.

RENDERED Equations:
When $a \ne 0$, there are two solutions to $ax^2 + bx + c = 0$ and they are
$$x = {-b \pm \sqrt{b^2-4ac} \over 2a}.$$

Great, so now I can make posts with simple matrix equations if necessary.

Latest News from Chemical and Engineering News

2012-01-10T07:15:00.000-08:00

To start the new year we look at the headlines related to nucleic acids in Chemical and Engineering News.
In the first week of the year two nucleic acid notes have been written in C&EN. One concerns genetic engineering modifying DNA sequences by using Zinc-finger nuclease proteins, and the other also concerns genetic engineering but this time at the expression level by suggesting a protocol to program gene expression using so-called "RNA-devices".

Targeted chromosomal duplications and inversions in the human genome using zinc finger nucleases
Hyung Joo Lee et al.
Genome Research advanced publication (2012)

Jin-Soo Kim and coworkers at Seoul National University have designed Zn-finger nucleases that target specific genomic sequences in human embryonic kidney cells and are able to induce sequence duplication and inversions.

Model-Driven Engineering of RNA Devices to Quantitatively Program Gene Expression
James M. Carothers, et al.
Science334 1716-1719 (2011)

The following is just a copy and paste of the abstract from the article due to how hermetic it seems to my understanding.
"The models and simulation tools available to design functionally complex synthetic biological devices are very limited. We formulated a design-driven approach that used mechanistic modeling and kinetic RNA folding simulations to engineer RNA-regulated genetic devices that control gene expression. Ribozyme and metabolite-controlled, aptazyme-regulated expression devices with quantitatively predictable functions were assembled from components characterized in vitro, in vivo, and in silico. The models and design strategy were verified by constructing 28 Escherichia coli expression devices that gave excellent quantitative agreement between the predicted and measured gene expression levels (r = 0.94). These technologies were applied to engineer RNA-regulated controls in metabolic pathways. More broadly, we provide a framework for studying RNA functions and illustrate the potential for the use of biochemical and biophysical modeling to develop biological design methods."

Weekly RNA News - Week LI - December 2011

2011-12-19T06:41:00.000-08:00

Top News of the Year.
According to Chemical and Engineering News

- Spliceosome Assembly Tracking by New Fluorescent Microscopy Technique
Melissa J. Moore at U. Mass. Medical, Jeff Gelles at Brandeis, Virginia Cornish at Columbia.
http://dx.doi.org/10.1126/science.1198830

These researchers use a new spectroscopic technique called Colocalization Single-Molecule Spectroscopy (CoSMOs) to track the dynamics of formation of the spliceosome. They corroborate what has been proposed before where the order of association of the spliceosome on the pre-mRNA is U1 -> U2 -> tri-snRNP (U4/U6.U5) -> NTC (multiprotein Prp 19-complex)
To summarize nothing better than their own mechanistic picture with estimated first order reaction constants.

So. I have been looking for the molecular weight of the Spliceosome for a while now and can't find it. I find that parts of it are around 200kDa, but I don't even know how much the so-called tri-snRNP assembly weighs. If you find it I would appreciate your feedback very much. The prokaryotic ribosome weighs about 2600 kDa.

- Modified Citosine
Guo-Liang Xu from Academy of Science of China and Chuan He from Chicago U.
http://dx.doi.org/10.1126/science.1210944

Evidence for Tighter Wrapping of DNA upon Methylation.
According to Chemical and Engineering News

On the science and technology concentrates from this week on C&EN, work on changes on DNA wrapping around the nucleosome are reported. The work comes from researchers Ju Yeon Lee and Tae-Hee Lee at Penn. State. In the article titled "Effects of DNA Methylation on the Structure of Nucleosome" http://dx.doi.org/10.1021/ja210273w published in the Journal of the American Chemical Society

Weekly RNA News - Week L - December 2011

2011-12-12T09:54:00.000-08:00

Is Arsenic-DNA Possible?
A Controversy is Born.

For better or worse Felisa Wolfe-Simon, a research fellow at NASA's Astrobiology unit became a scientific celebrity a year ago. In an express paper to the highest ranked North-American journal, that is, Science, Dr. Wolfe-Simon (who received her PhD from Rutgers in Oceanography) reported, along with her collaborators that:

"A Bacterium Can Grow by Using Arsenic Instead of Phosphorus"

The bacterium was taken from Mono Lake, California, a "hypersaline and alkaline environment", as reported in the Science paper http://dx.doi.org/10.1126/science.1197258.
In the time since the express publication a number of papers have been written for, against, and in a neutral tone regarding the reported observations.

I find it interesting that before December 2010, that is, the date of the express report, Dr. Wolfe-Simon was already reporting along with Paul C. W. Davies (why is this name familiar?... ohhh, is the same guy of Superforce, the best-seller layman book on unification theory, a kind of Isaac Asimov guy!) on the Arsenic conjecture in a paper with the very suggestive title "Did Nature Also Choose Arsenic?" in the International Journal of Astrobiology, 2009, 8, 69-74.

Another one of the past collaborators of Dr. Wolfe-Simon and also a researcher at NASA's Astrobiology, but not a coauthor on the Science paper, that is, Steven A. Benner (not to be confused with Steven Brenner @ U.C. Berkeley) wrote a nice commentary (http://dx.doi.org/10.1126/science.1201304) about the published paper. He highlights how the main problem with an arsenate-diester would be its estimated half-life in water, which, by back-of-the-envelope calculations, leads to a half-life which is too short (About 1 minute) compared to that of the phospho-diester backbone in DNA (About 30 million year). He also proposes and experiment which I'm sure a lot of researchers thought of when eyeing for the first time the Arsenic life report, that is, to use an Arsenic isotope.

One of many papers (http://dx.doi.org/10.4161/adna.2.1.15509) with some criticism is that of Frank-Kamenetskii of B.U published in a new journal named Artificial DNA, whose chief editor is PNA (Peptide Nucleic Acids) main-man Peter E. Nielsen, here it is:

"After all, recent history has taught the scientific community to be very skeptical to any unusual claim, especially appearing in such high-profile journals like Nature and Science. It suffices to mention the most recent embarrassment with publication in Science, with loud fanfares, of an article about “arsenic life”.
Once someone reads carefully the article and supporting data, it becomes clear that the data by no means support the claim that arsenic substitutes phosphorus in DNA of a bacterial strain obtained by the authors."

On the other hand theoreticians and modelers have not been shy on jumping right into the problem, two examples are the publications by Liz Denning at Alex Mackerell group in Maryland (http://pubs.acs.org/doi/abs/10.1021/ja201213b) and Jiri Sponer's group at Brno, Czech Republic (http://dx.doi.org/10.1021/jz200015n).

In conclusion, this story just gets more interesting as it ages. On a personal note I would have to say that on my first read of the paper my thoughts were very close to those of the wise Maxim, but now I'm not so sure and see a window of possibility on this most interesting result. Only time and hopefully Felisa Wolf-Simon will be able to wrap-up this story on whether she's found a very interesting extremophile, or an alien living among us.

Weekly RNA News - Week XLIV - November 2011

2011-11-21T00:26:00.000-08:00

Meni Wanunu, Swati Bhattacharya, Yun Xie, Yitzhak Tor, Aleksei Aksimentiev, and Marija Drndic
Northeastern, Uni. Illinois and UCSD
Nanopore Analysis of Individual RNA/Antibiotic Complexes.

Nanopores in thin solid-state membranes are used to rapidly analyze individual RNA/drug complexes. The interactions of a truncated A-site RNA model of the prokaryotic ribosome with aminoglycoside antibiotics are characterized by passing individual molecules through a 3–3.5 nm diameter pore fabricated in a 8–10 nm thick silicon nitride membrane. Complexes of the A-site RNA with aminoglycosides can be distinguished from unbound A-site based on the ion current signatures produced as they pass through the nanopores. Counting the fraction of free and drug-bound molecules affords label-free drug–RNA binding isotherms consistent with literature reports and with data generated using independent fluorescence-based assays. Our measurements are supported by molecular dynamics simulations, which illustrate the relationship between the ionic current and complexation of the A-site RNA with paramomycin, a prototypical aminoglycoside antibiotic.

http://dx.doi.org/10.1021/nn203764j

Weekly RNA News - Week XLIII - November 2011

2011-11-15T03:56:00.000-08:00

Lately I have been late on my weekly posts, so, for now I will only put some brief news until I find the time to write better posts.

- According to experiments carried out by Victoria Jeanne DeRose , Alethia A. Hostetter , and Maire F. Osborn from the University of Oregon, there is more cisplatin acumulation in total RNA in yeast than in total DNA in yeast.
http://pubs.acs.org/doi/abs/10.1021/cb200279p

- Researchers Jeremy E. Wilusz, Joseph M. Whipple, Eric M. Phizicky and Phillip A. Sharp, from the MIT and Uni-Rochester have found that tRNAs marked with CCACCA are targeted for degradation.
http://www.sciencemag.org/content/334/6057/817.abstract

- Antony M Jose, Giancarlo A Garcia and Craig P Hunter.
Harvard and U.Maryland.
Two classes of silencing RNAs move between Caenorhabditis elegans tissues
http://www.nature.com/nsmb/journal/v18/n11/full/nsmb.2134.html

- H. James Tripp, Ian Hewson, Sam Boyarsky, Joshua M. Stuart and Jonathan P. Zehr
UCSC and Cornell
Misannotations of rRNA can now generate 90% false positive protein matches in metatranscriptomic studies.
http://nar.oxfordjournals.org/content/39/20/8792.short?rss=1

-Lipfert J, Kerssemakers JJ, Rojer M, Dekker NH.
Delft Uni. Netherlands
A method to track rotational motion for use in single-molecule biophysics
http://www.ncbi.nlm.nih.gov/pubmed/22047303

Weekly RNA News - Week XXXVII - September 2011

2011-10-17T04:34:00.000-07:00

New Structures in PDB

A new 70S ribosomal structure was released to the Nucleic Acid Database this week with PDB_ID:3zvo. The ribosome structure has a release factor protein attached to it. This release factor is called release factor 3. The structure is coming from Ramakrishnan's group and in line with their previous work it's a ribosome extracted from the Thermus Thermophilus extremophile bacteria which lives in hot springs.

The new structure has a 3.8 Angstrom resolution, so perhaps a little bit above the cutoff resolution for the rnasteps database.

From the new structures pouring into the PDB this past week here is a movie of Mss116p (NTE deletion) bound to ssRNA and AMP-PNP.

The PDB_ID for this RNA chaperone is 3sqx.pdb.
The chaperone functions in splicing mitochondrial group I and group II introns.
The movie is not very nice since I'm still learning which video format will be preferred by blogger.

Weekly RNA News - Week XXXVI - September 2011

2011-09-23T08:11:00.000-07:00

Not One but Two!, Recent Reviews on RNA Structure, Interactions, and Folding Principles.

Two reviews have just come out from the Mondragón group at Northwestern and from the Pyle group at Yale.

Emerging Structural Themes in Large RNA Molecules
Nicholas J. Reiter, Clarence W. Chan and Alfonso Mondragón
Current Opinion in Structural Biology 21, 319-326 (2011)

In line with their previous research (i.e. the RNase P X-Ray structure, PDB_ID:3Q1Q) the authors stick to reviewing what has been learned from intermediate size RNA molecules, that is, RNA molecules larger than a hundred nucleotides, but smaller than say a thousand nucleotides.

The main points argued in this review are:

- RNA's of this size are relatively flat due to tertiary interactions, namely, "extensive" coaxial stacking, loop-loop interactions, and not mentioned in the review side by side helical arrangements.
- The structures of the functional cores of intermediate size RNA's are conserved, not necessarily the sequences.
- The functional cores don't need large conformational arrangements, they are said to be preassembled and usually this happens around a metal ion.
- Molecular recognition of "targets" is accomplished by shape-complementarity and specific atomic interactions (base-pairing, base-stacking, base-sugar, base-backbone). This is a general principle in molecular recognition.
- Adenine's are statistically more abundant than any other base in tertiary interacting regions, they are also the most conserved in all RNase P's.
- Proteins extend the functionality of RNA's and can be essential as in the case of the ribosome and the spliceosome, or non-essential, as in the case of RNase P and Group I and II Introns.

They conclude that the best is yet to come concerning RNA's in line with the promise, highly encouraged by Breaker's Lab. research, that many more RNA structures are to come and then this few empirical facts we've come to know will expand or change accordingly.

For the Group II Intron one can have an image like the above one, showing the helical regions as blue cylinders and the phosphates colored grey connected with a string in red, to illustrate the "flatness" of intermediate sized RNA's.

The Molecular Interactions That Stabilize RNA Tertiary Structure: RNA Motifs, Patterns, and Networks
Samuel E. Butcher and Anna Marie Pyle
Accounts of Chemical Research X, xxx-xxx (2011)

Interestingly enough the previous paper (the one of Reiter) comes from a whole issue devoted to nucleic acids and edited by Anna Pyle.

In this review Butcher and Pyle take a look at the main interactions and structural elements found in RNA's today.
These seem to be split into:

- Coaxial Stacking of Helical Regions.
- Geometric Organization of Helical Junctions.
- Long-Range Interactions of Watson-Crick Base-Pairs.
* Kissing-Loops.
* Pseudoknots.
- Minor Groove Triples and A-Minor Motifs.
- Kink Turns and Other Turn Motifs.
- Tetraloop-Receptor Motifs.
- Intercalation Motifs (T-Loops).
- Triple-stranded RNA's (more like RNA triplets)
- RNA Quadruplexes.

The final remarks on the review concern the nature of the ribose, the 2'-OH interactions (e.g. Ribose Zippers), metal ions (the description of new crystallographic results in accordance to Draper's seminal paper reviewed in this here blog) and non-canonical base-pairs.

In Figure 2 of the article an image of a kissing-loop interaction is shown. The following image reproduces such image with helical regions identified by 3DNA represented as blue cylinders.

Weekly RNA News - Week XXXV - September 2011

2011-09-13T06:26:00.000-07:00

RNAase P: At Last, the Key Finds its Lock
Benoit Masquida and Eric Westhof
RNA 7, 1615-1618 (2011)

Masquida and Westhof who are both at Strasbourg, France, review the X-ray structure obtained with a resolution of 4.2 Angstroms of RNase P, a ribozyme like the ribosome which has the ability to work as a "multiple turnover" enzyme. The structure of RNase P has PDB_ID's: 3Q1Q and 3Q1R, the difference is that the second one contains the 5'-leader whereas the first comes without, and at 3.8 Angstrom resolution.
The structure was determined by a group of researchers at Northwestern University and the University of Chicago and the main author is Nicolas Reiter who is a post-doctoral researcher at Alfonso Mondragon's Lab at Northwestern. The reason for the review is mainly that Tsai, Masquida, Westhof and others proposed a structure for RNase P in 2003 from secondary structure maps enriched with hydroxyl-radical footprinting data and it's quite close to the final crystal structure. A pymol generated figure showing the full holoenzyme is drawn below:

Notice the 5'-leader is rendered as spheres with carbons in grey color and just in top of the protein part (drawn in black) of the holoenzyme (holoenzyme=enzyme+cofactors). The surface in blue is just given the name P-RNA, and the part rendered as sticks is pre-tRNAphe. The whole structure has a total of 423 bases coming from the P-RNA and the pre-tRNAphe.

Weekly RNA News - Week XXXIV - September 2011

2011-09-08T03:18:00.000-07:00

From Structure Prediction to Genomic Screens for Novel Non-Coding RNAs
Jan Gorodkin and Ivo L. Hofacker
PLOS Comp. Bio. 7, e1002100 (2011)

This is one of those cases where an article defies the traditional classification. By this I mean that although this article is clearly a review, it is not being published in a review journal, or maybe it's more likely that I don't understand the format of how PLoS works, for example their dislike for the traditional page-numbering scheme.
~~OK, stop ranting about irrelevancies and stick to the article.~~
~~Ohh, well, I can't stop with the "irrelevancies".~~
I guess it's the model of PLoS which makes articles hard to read, yes, an unfair judgement based on one article which you were expecting to be great (due to the authors) and then you're thoroughly deceived by the many errors and the lack of depth of the content, specially when compared with their much nicer article "De novo prediction of structured RNAs from genomic sequences" published in Trends in Biotechnology, a "regular" type of journal without the PLoS hype.

The article main topic is that of "de novo" discovery of non-coding RNA's. To this end the authors highlight two main strategies.

1) Sequence based alignments.
2) Synteny/Orthology with structure realignment.

Strategy one doesn't need much explanation, just that databases of know RNA sequences are necessary to make comparisons across organisms, for example the Rfam (RNA-families) database.
The second case brings up jargon, and it's not clear what they might mean if one sticks to the wikipedia definition of the term synteny. It would be nice if there was an example of what they mean in practice. What I understand is that perhaps in the second strategy secondary structure alignments are taken into account in the context of distant regions in the same chromosome which might refer to the "same" gene.

BlastR—fast and accurate database searches for non-coding RNAs
Giovanni Bussotti and Emanuele Raineri and Ionas Erb and Matthias Zytnicki and Andreas Wilm and Emmanuel Beaudoing and Philipp Bucher and Cedric Notredame
Nucleic Acids Research, 39, 6886-6895 (2011)

The main idea of this article is to use the already existing techniques for alignments of proteins to the alignment of RNA's. To test the perl script they have implemented to interact with the already existing ncbi-blast package I downloaded the full long-non-coding RNA database from :
http://www.lncrnadb.org/
And then I used it as database to compare, say, one of the sequences existing in such database.
Not surprisingly the result is a 100% score in their similarity measure, and it took a couple of hours to get it all done. Here's a snapshot of the results of running the command:

blastallR.pl -p blastr -i NR_003141.3 -d database/ncbi_blastR_format/db -m 8

Not surprisingly the first score matches as indicated by the 100% score.

Weekly RNA News - Week XXXIII - August 2011

2011-08-23T06:34:00.000-07:00

It's amazing what a very simple molecule can do. In this case I am talking about 1-Aminoanthracene. I think any chemist, and even non-chemists will be able to draw this simple molecule, yet, very few would be able to tell you that you can make the spinal cord of a tadpole light-up when it has ingested the molecule. Such is the image presented to us in the latest issue of Chemical and Engineering News. Yes, this is where one so easily falls in love with science. Simplicity at its best. This certainly is one beautiful way to obtain powerful insights into nature.

Here's a copy of the image which has been made by Daniel Emerson at Ivan J. Dmochowski's lab at U.Penn in Philly:

The original article was published in the Proceedings of the National Academy of Sciences of the U.S.A.

Carbonaceous Meteorites Contain a Wide Range of Extraterrestrial Nucleobases
Michael P. Callahana and Karen E. Smith and H. James Cleaves II and Josef Ruzicka and Jennifer C. Stern and Daniel P. Glavin and Christopher H. House and Jason P. Dworkin
PNAS, XX, XXX-XXX (2011)

Back to a claim of old, that of finding nucleobases in meteorites. The difference in this study seems to be that of finding some derivatives of purine which are not present in earth nor in the surroundings of the surveyed meteorites. This reminds me of reading the older papers of Dworkin on the possible synthetic routes of this babies in a pre-RNA world.

Weekly RNA News - Week XXIX - July 2011

2011-07-25T23:45:00.000-07:00

RNA is back in the front page news of "The New York Times".
A note by some guy called Dennis Overbye is bringing back news on RNA to the front pages. Well, really the news are not so new, but it's good to see that folks are still interested in the origin of life, of course, this is not at all to be unexpected since the main "hot-shot" in the article is Gerald Joyce, and yes, if that name rings a bell it's because is intimately associated with that of the great Leslie Orgel.
Joyce might have been the favorite grad. student of Orgel, and, actually must consider himself quite lucky since Orgel liked to work alone and seldom gave the privilege of coauthorship. Now, what's interesting is that, even though the article is well written and well informed and gives good credit to people like Alex Rich, it also states:

"The first inhabitant of this Eden, chemists suspect, was RNA"

And doesn't even give a small paragraph to say, that chemists also suspect that it could have been a pre-RNA molecule.

Evidence for a thermodynamically distinct Mg2+ ion associated with formation of an RNA tertiary structure
Desirae Leipply and David E. Draper
JACS, XX, xx-xx(2011)
Nice article showing a technique to be able to distinguish two types of association of Mg2+ ions to RNA.
The main idea the article exposes is that Mg2+ ions can interact with RNA's in two ways. In most cases they can form an ion atmosphere (purple haze in image) around the RNA, and in other cases they can get stuck in confined regions (site-bound - brown dot in image) and as such are considered as chelators.

They propose experiments where the free energies of these different ways of binding can be determined.

In the next image the larger green sphere represents a Magnesium site-bound to RNA. The purple, larger sphere is potassium also site-bound, and the surface is the solvent accessible surface mapped with the color of the electrostatic potential. In the right the secondary structure corresponding to structure PDB_ID:1hc8

Effect of Locked Nucleic Acid Modification on Thermal Stability of Non-canonical DNA Structure
Bhattacharyya J, Maiti S, Muhuri S, Nakano SI, Miyoshi D, Sugimoto N
Biochemistry, XX, xx-xx(2011)

A fast look at this paper shows that there are no references whatsoever to the structural work either from modelling studies of Pande and Nilsson, or to the experimental one of Eichert, Forster and collaborators.
Perhaps since they've focused their attention in parallel instead of the more common antiparallel strands, then they didn't worry so much about LNA studies on antiparallel DNA strands.

Weekly RNA News - Week XXVIII - July 2011

2011-07-21T08:29:00.000-07:00

The Endless Subtleties of RNA-Protein Complexes
Eric Westhof and Valerie Fritsch
Structure, 19, 902-903 (2011)

As in other occasions the authors give a good idea of what is to come in the field of RNA, or at least, what would be nice to see coming. In this case they comment on the work done at Juli Feigon's lab at UCLA on the interaction of a protein which binds a double-stranded RNA region of around 14 base-pairs and which contains two G.U wobble base-pairs and is flanked by a tetraloop. Westhof and Fritsch mention two tricks by which proteins can recognize double-stranded RNA helical regions. One is that the helical region per-se is "altered" from a canonical Watson-Crick paired one through bulges in the helical stem or non-canonical pairings modulating it's major groove so that it looks more like a B-DNA conformation one, that is, one which is wider and not as narrow, allowing for sequence recognition. The second trick, and which is the one adopted by the dsRBD (double-stranded RNA Binding Domain) of the reviewed NMR structural work, is that of interacting with the single nucleotides of the loop region. The Feigon lab. work shows how a tetraloop with a different sequence than the "canonical" AGNN one, but which accomplishes a very similar three dimensional fold, can also be bound by the dsRBD showing that not all can be predicted through RNA sequence alone, but that structural data is essential for understanding the details of protein-RNA interactions.
The Structures under PDB_ID: 2LBS have not been released yet.

Weekly RNA News - Week XXII - June 2011

2011-05-31T00:15:00.000-07:00

Halima Mouhib and Wolfgang Stahl and Monique Luthy and Michelle Buchel and Philip Kraft @ Germany and Switzerland.
Cassis Odor through Microwave Eyes: Olfactory Properties and GasPhase Structures of all the Cassyrane Stereoisomers and its Dihydro Derivatives.
Angewandte Chemie International Edition, 50, 1-6 (2011)

I came across this article while reviewing the Chemical and Engineering News of this week.
What seems interesting about this publication is that such a small conformational change can affect drastically the chemical reactivity, and directly the human sense of smell, also, since these conformational changes in sugars are seen in RNA, then it's just a related story that seems, whatchamacallit, cute.
I can't help but to like that they use correct CPK colors, yes, what do u know, carbon is black, victory!, and also that they seem to be using pymol. Paying attention to the references at the end of the paper perhaps the images were done with Accelerys discovery studio.
But wait, don't be too emotional and pay attention to detail. Actually it is not all a conformational effect. The isomer which has a more fruity character is a DIHYDRO derivative.

Weekly RNA News - Week XII - March 2011

2011-04-05T10:40:00.000-07:00

A. Vazquez-Mayagoitia and S.R. Horton and B.G. Sumpter and J. Sponer and J.E. Sponer and M. Fuentes-Cabrera
Ab-initio modeling of a possible prebiotic reaction favors ribose over other possible sugars.
Astrobiology, 11, 115-121 (2011)
Many of us like to munch from time to time into the big question. That of the origin of life. Frankly, my guess is that anyone who works with RNA at any level is always tickled, to varying levels, by the big question. The authors of the referenced paper show a detailed quantum mechanical Ab-intio study on a so-called "silicate-mediated formose reaction" which, they show, by energetically favoring arguments, prefers ribose over other sugary options.

Robert V Brown; Laurence H Hurley @ Uni. Arizona
A Review of Cases where DNA might act like RNA
Biochemical Society Transactions, 39, 635-640 (2011)
A fun review mainly concerning the G-quadruplex and how this, and other DNA conformations with loops, for example, might behave in a similar fashion to RNA. It´s interesting to see their reproduced graph of the relation between G-quadruplexes and cancer.

Weekly RNA News - Week XI - March 2011

2011-04-05T08:55:00.000-07:00

Jun Feng and Nils G. Walter and Charles L. Brooks, III @ University of Michigan
All-atom Go model study of preQ1 riboswitch aptamer domain folding.
Journal of the American Chemical Society, 133, 4196-4199 (2011)
Feng, Walter and Brooks present interesting results using a Go model for simulating the folding of an RNA sequence into a riboswitch aptamer in the presence of a metabolite called preQ1. The model used seems to favor a description of a funnel shaped free-energy landscape for the folding of this RNA riboswitch. It's interesting to see that what is described as a structure made of two helices called P1 and P2 could also be described as an "irregular" triple-helix:

Some very interesting thoughts come out from reading this article. The folding of this riboswitches must be pretty fast, pico, nano seconds? so, these are good cases for performing MD simulations. In general the folding of parts of mRNA into structured regions seem to be good targets for MD research. I also wonder if the methodology used can take into account the possibility of having a rugged RNA folding landscape and if such case would influence the sequential and cooperative folding mechanism results.
Other things which would be interesting to see are the electrostatics of the A-tract of the folded configuration, for example.

Martin Mann and Konstantin Klemm @ Freiburg & Leipzig
Efficient exploration of discrete energy landscapes
Physical Review E, 83, 1-7 (2011)
The authors use a so-called number partitioning problem, which is common in computer science, to be able to stochasically sample the free energy landscape of RNA secondary structures.

Weekly RNA News - Week X - March 2011

2011-03-10T01:39:00.000-08:00

Scott, Coyle, and Doudna @ Berkeley
Xrn1: Structure of a messenger RNA degrading enzyme in complex with three DNA thymines.
Molecular Cell, 41, 600-608 (2011)

The Doudna lab comes again with another interesting structure related to RNA mechanics. As Scott, Coyle, and Doudna say in their paper, there is only one enzyme with the task of degrading mRNA in the cytoplasm of eukaryotic cells, this enzyme is called Xrn1, which sounds a lot like a sci-fi movie to me. They also say that the enzyme weighs 175 kDa, and is conserved from yeast to mammals. In order to crystallize the structure they used DNA instead of RNA. This you can see in the structure with PDB_ID:2Y35. The idea of the trick is that it takes longer for Xrn1 to degrade DNA than RNA, and the mechanism of degradation is assumed to be similar enough to that of an mRNA since it is based mainly on recognition of an RNA substrate "marked" by a 5'-monophosphate.

In the following image you can clearly see how Histidine 41 and Triptophane 540 kind of make a stacking trap of the three thymines, you can also see in the right part of the image the clear hole where the mRNA must come in and out from, I guess:

Figure four of their article shows the full mechanism they propose for the process of mRNA decay as a four step process of Binding, Hydrolysis, Thermal Breathing, and Translocation.

McCown, Roth and Breaker @ Yale
More glmS ribozymes identified via sequence-structural consensus and with the addition of this ones a new (refined) consensus is suggested.
RNA, 17, 728-736 (2011)
By using the infernal software which looks at sequence consensus and secondary structure consensus they identify more possible candidates for a type of ribozyme. This ribozyme is called glmS, and it's found in prokaryotes.
It seems like this ribozyme is located at the 5' un-translated region (UTR), of mRNA, but, it does assume a 3D-fold. Targeting this ribozyme with antibacterial drugs might result in the control of expression of peptidoglycan and extracellular lipopolysaccharides, which, I'm guessing, must be essential for having a functional prokaryote bacteria.
In general, the article goes along the main proposal or idea of Breaker that there are many 3D structured RNA's that we still don't know much about.

Fang, Yoﬀe, Gelbart, and Ben-Shaul @ UCLA and Hebrew Uni @ Jerusalem
Another secondary structure folding algorithm where sequential folding starts after locating the duplex (base-pair) which results on the largest possible single stranded loops.
J. Phys. Chem. B, XX, XX-XX (2011)
Perhaps the best way to describe this new algorithm for secondary structure prediction is by using their main figure reproduced here:

Weekly RNA News - Week IX - March 2011

2011-03-01T05:25:00.000-08:00

Mackay @ U. Sidney, Font and Segal @ UCDavis
The Prospects for Designer Single-stranded RNA-binding Proteins (RBP)
Nature Structure and Molecular Bio., 18, 256-261 (2011)
There are an array of possible uses that RNA-binding proteins could be engineered for. The following figure in their publication makes a nice review of such possibilities.

In their review they show that there are mainly four classes of RBP's. They are called RNA recognition motifs (RRM), Pumilio repeat domains (PUF), human heterogeneous nuclear ribonucleoprotein K homology (KH), and zinc-fingers (ZF). Of these proteins so far the most efficient in recognition are the PUF ones, but the authors point out that this might be due to the infancy of the field.
They also mention the possibility of having proteins that bind to double-stranded RNA's, like the ones present in viruses and in the "new" RNA world of small interfering RNA's and micro RNA's, but focus their attention on single stranded RNA binding, which makes sense if one wants to target mRNA.
I find this review very interesting since in the greater sense it implicitly says that this is a way to bring back the game to proteins. Just by looking at their very neat figure for possible protein-ssRNA interactions one just can't help to wonder that the yellow blob, instead of being a protein, could be an RNA, a DNA, a PNA, or a modified nucleic acid.

Weekly RNA News - Week VIII - February 2011

2011-02-23T02:22:00.001-08:00

Various authors and N. Ban (ETH) and J. Doudna (UCBerkeley)
Signal Recognition Particle (SRP) in complex with receptor (SR) at 3.9 Angstrom
Science, 331, 881-886 (2011)

Still an unreleased structure in the Protein Data Bank but will be coming out soon.
The Signal Recognition Particle is an RNA-protein complex which delivers at the time of translation (co-translationally) membrane and secretory proteins. The SRP is made of a surprisingly long double stranded RNA, I wonder if it stays "straight" thanks to the aid of the protein, and why would it want to do that?

A. Robbins-Pianka and M. D. Rice and M. P. Weir @ Wesleyan, Connecticut
Translation initiation sites (TIS) are influenced by secondary structure downstream and upstream of this sites in highly expressed genes.
Bioinformatics, 26, 2651-2655 (2011)

The results are clearly explained in their abstract:
"Trends in base composition and base-pairing probabilities suggest that efficient translation initiation and high protein expression are aided by reduced secondary structure upstream and downstream of the TIS. However, the downstream reduction is not observed for sets of TISs with nucleotide sequence contexts unfavorable for translation initiation, consistent with previous suggestions that secondary structure downstream of the ribosome can facilitate TIS recognition."
And in the following figure:

Weekly RNA News - Week VII - February 2011

2011-02-21T14:08:00.000-08:00

Bujnicki Lab @ Poznan - Poland
ModeRNA python based software for RNA fold prediction.
NAR Advanced Publication. February 2011

A new software for RNA structure prediction from sequence given the existence of a structure with similar sequence is out, it's called ModeRNA and is somewhat similar to what the MC-Fold MC-Sym pipeline of Major does or the s2s, assemble "pipeline". The article has a nice up to date review on what is out there for RNA structure prediction. Published ahead of print in NAR.
You can find it online at: ModeRNA.
The last update on the software was done in november last year.

Xiao Group @ Hubei - China
Guided manual adjustment of atom clashes and atom stretches on RNA reconstruction.
JBSD 28 675-843 (2011)

Sometimes nice papers, at least from the creative point of view, go to the journals with, perhaps, not such big impact factors but strong traditions behind. I'm liking more and more some of the papers in the journal of biomolecular structure and dynamics, specially if the big shots are not the main authors. I liked the article by Zhao Y, Gong Z and Xiao Y. in JBSD 28 815-26, (2011).

Dill Group @ UCSF - USA
A so called semi-explicit solvation model which aims to be analogous in results to explicit solvation but consuming a much shorter computer time.
PNAS ahead of print February 2011

Not precisely RNA news, but an interesting method that could be applied to RNA's since it's a general solvation method.
The main idea is (coherent with Dill's group work) to think about "partition theory" type ideas, that is, we assume that the total free energy of a process can be split into additive contributions. In this case Fennell, Kehoe, and Dill propose that the free energy of solvation can be split into three components, a non-polar one, and two electrostatic polar components, one due to a first solvation shell, and the second due to the remaining bulk effect. The practical trick to do what they call semi-explicit assembly (SEA) is a four step process as clearly illustrated below:

Weekly RNA News - Week VI - February 2011

2011-02-10T02:07:00.000-08:00

Dekker Lab.
Nano-sized quartz cylinders for force-extension experiments.
ACS Nano. 2011 Jan 31 ahead of time.

In the Dekker lab. in the Netherlands they're now using electron beam litography to make nanometer sized cylinders and truncated cones made of quartz for use in single molecule experiments, for example for use in force extension experiments of DNA or RNA.
Dekker lab. has already provided some nice results on measurement of the persistence length of double-stranded RNA of around 640 Ångström using magnetic tweezers and compliance to the Worm-Like-Chain model.

Sarah Woodson and Eda Koculi
Review on native polyacrlyamide get electrophoresis (PAGE) on RNA.
Methods in Enzymology, Volume 469, 2009, Pages 189-208

My reviews are mainly based on what I get fed to me trough automatic periodic searches for favorite authors and topics in pubmed, and also from periodic flash reviews of the headliners related to RNA of the big journals from the US and GB. Sometimes what pubmed sends is outta sync, that is, this review is a 2009, still valid though.
It actually has some very, very, nice and simple gels which can be read in quite the clean manner. In the gel in the upper part of the image the part marked by P4-P6 refers to a catalytic RNA of the so called group I intron type, the U1 and U2 lines are constructs where the RNA sequence has been modified, that is, these are mutants. We can infer a structural change due to the sequence modification by the difference in the migration on the gel of the mutants and the original. In the lower part of the image a very interesting fact of RNA is shown, that is, RNA while folding can easily be "trapped" into intermediate folds (denoted by I) before getting to the most stable or native (denoted by N) one. We can also see that a mutated RNA (L2L5cP3) can fold faster into an "intermediate-free" lane in comparison to the wild type (wt).

It is interesting to see that in the same journal-book Dave Lilley also has some very nice experiments for what can be learned from RNA helical junctions from gels.
And not only does Sarah Woodson have the previous review but there is another one regarding OH radical footprinting in vivo using X-Ray. While refreshing what I understood of OH radical footprinting I found the following Tom Tullius quotation:

"Because the hydroxyl radical is an extremely reactive and non-discriminating free radical, the site of attack has no dependence on the base sequence of the nucleic acid. Instead, the susceptibility of a particular nucleotide to hydrogen abstraction is governed by its accessibility to solvent. This property makes the hydroxyl radical footprinting method the experimental equivalent of a calculated solvent-accessible surface area of a nucleic acid molecule"

Weekly RNA News - Week V - February 2011

2011-02-09T04:09:00.000-08:00

Some weeks ago in Chemical and Engineering News there was a story about Roche pulling out of development of RNAi based drug research. Now there is a new article in C&EN talking about progress being made by some companies on RNAi, and the still latent preoccupation by RNAi pharma researchers on such a large move by Roche.
C&EN show a nice table citing the following companies having ongoing RNAi pipelines:

Alnylan
Calando
Marina Biotech
RVi
Silence Therapeutics
Tekmira

What has first impressed me greatly about these companies is the great level of their webpages. I expected older css and perhaps old flash kinda pages. But the majority of these ones look very html5 css3 like, quite stylish IMHO.

It's amazing what "good" publicity can do. If I wasn't a scientist and just wanted to invest some bucks on pharma startups, I would probably not invest in say, tekmira, which has the least "pretty" page on my superfluous 3s judgment.

Not three years have gone by since the publication of the Parisien and Major paper (Nature 1998) which, to my knowledge, is the first fully automated from sequence to 3D structure simulation of RNA, and the RNA structure prediction field sounds as if it was an already consolidated thing. There is a nice paper by Polish researchers on what there is out there and how it compares to protein folding prediction strategies. They have a table with the reviewed software and for RNA they mention RNABuilder, ModeRNA, Vfold, DMD, HiRE-RNA, MC-Fold, SimRNA, and CG. ModeRNA is the one developed by the authors of the review.

Weekly RNA News - Week IV - January 2011

2011-01-26T08:23:00.000-08:00

Yelena Koldobskaya @ U. Chicago and collaborators propose a new method to crystallize RNA's using chaperones:
NSMB January 2011

There is a protein called Signal Recognition Particle (SRP), it's made of a protein part and a 4.5S RNA. This protein is important in the mechanism of action of the ribosome and Leandro F. Strozi at Grenoble and collaborators have "describe the cryo-EM structure of the E. coli ribosome–SRP–FtsY complex in the early conformation, demonstrating that the ribosome acts as a platform that optimally positions critical SRP regions for receptor recruitment":
NSMB January 2011

The third week of January came with a special issue on surface chemistry in PNAS.
Two interesting articles, one mentions what has been learned using DOS analysis from DFT calculations on surface catalysis, and another a general review on surface processes and the need for taking into account the nucleus, not just electronic structure.
PNAS on Surface Chemistry

Locked nucleic acids (LNA) can be interpreted via rigid blocks too

2010-11-12T07:01:00.000-08:00

A new crystal structure (NAR, 2010, 38, 6729) shows a representation of locked nucleic acids using the rigid-body parameter formalism imbeded in 3DNA. It's interesting to see that stretching this type of data in an orderly study one could even get to compute global properties of LNA's ala PNAS 98 paper of Olson, Gorin, et al.
It's also fun to redo their images into a prettier picture accompanied by numbers and compare the numbers to what happens with RNA conformations, and also with DNA conformations. The other way I've seen to modulate helical stretches of nucleic acids is with aptamers like the one of a previous post.

RNA Helix Junctions

2010-06-01T08:02:00.001-07:00

To understand RNA we need first to split it into two main regions, that is:

1) Single strand.
2) Double-strand helical regions.

This has been known for quite a while now, and so people have done quite a good job at describing double-stranded helical regions where there is canonical Watson-Crick base-pairing, that is, G pairs with C forming 3 hydrogen-bonds, and A pairs to U, forming 2 hydrogen-bonds. Now, the part that is always left a bit out of the picture, or which at least is less commonly looked at is the single stranded part of RNA.
Aalberts and Nandagopal from Williams College in Massachusetts are pointing out this problem, specifically in relation to secondary structure prediction algorithms.
They have refined mfold to take better account of hairpin loops and "multi-branch" loops. By including some type of self-avoiding freely-jointed chain model called FJC2 they give a polymer theory description of loops and claim to decrease the mfold error for multibranches 10 times.

Yet another paper which is also concerned with the interplay between single-stranded and helical regions is another one of the unstoppable paper making machine of the Czechs.

Besseova, Reblova, Leontis and Sponer publish in NAR ahead of print on May 27 a summary of MD simulation performed on three-way junctions picked from the ribosome. They characterize their main normal modes of motion in a fashion similar to what has been carried on by their group for other parts of the ribosome. Strangely they don't cite Christian Laing's latest papers on junctions, nor Dave Lilley's, not even on passing.

Here's a picture of one of their simulation snapshots:

PLASMA AND MAGMA, future keywords to keep in mind

2010-05-31T14:03:00.000-07:00

I had the great opportunity to attend a talk by Jack Dongarra in 2001 at a seminar-workshop at Merida, Venezuela, called Second Latin-American School on Parallelism and High Performance Computing. This was the first time I heard about the top 500 list of supercomputers, and also the first time I ever heard about grid computing, which has in a way evolved into cloud computing nowadays.
I remember that Dongarra's talk was one of my favorites because of its strong link to Moore's Law, and the prediction of the computational future as a simple power law. Since then, I've learned that I must change my laptop roughly every 14 months in order not to loose my investment completely, and also to be able to work competitively in my field, that of computational chemistry.
Due to a short news article by the BBC, I remembered, once again, the name of Jack Dongarra. When I googled "top500 dongarra" I stumbled upon a youtube talk at the University of British Columbia, I higly recommend watching it.

From the talk I learned that, if you do any kind of programming, and you do some sort of linear algebra operations in your code, you will inevitably have to move to PLASMA, that is, the new algorithms which take advantage of parallel execution, which is a growing need, according to the frequency limit on computer chips, clearly and neatly explained in Dongarra's talk at U.B.C.
Additional to PLASMA, we will have to learn MAGMA, that is, if we are going to use GPU's efficiently to solve computational chemistry problems, which brings to mind two relevant but naive questions:

1) Does the newly GPU implemented Amber 11 use MAGMA?
2) Would Dongarra be interested in having the generator matrices scheme for polymer modeling adapted to benchmark supercomputers? They already have gromacs and gamess in the fastest supercumputer, JAGUAR, so, why not?

Anyhow, I highly recommend periodically checking Dongarra's talks and ideas if you want a peek into the future.

Weekly Review / Monday May 17, 2010

2010-05-18T12:37:00.000-07:00

In PDB code 2KR8, one has an example of a K-turn motif. The authors of the study call it specifically a U4-Kt RNA. It seems like there are no specific structural studies of K-turn RNA not bounded to protein. The study which discloses this PDB structure says to be the first to shown an unbound Kt-RNA structure using NMR

The authors are based in Grenoble France and Heidelberg Germany and publish in Nucleic Acids Res. 2010 May 13

Turner Lab. just released a new reparametrization of the amber99 forcefield. They call it amber99chi. So, the name makes it obvious. It has been reparametrized to get the chi torsion angles right in RNA, and also it has been reparametrized to get the sugar puckering conformations of RNA right, or at least better than amber99. They compared the new force field with NMR data and get better agreement than with just amber99.
J Chem Theory Comput. 2010 May 11;6(5):1520-1531

Uracyl-Tetrad Stabilizes Guanine-Quadruplexes

2010-05-14T07:19:00.000-07:00

Simply put, the result shown in JACS that I want to blog about is the following:

"Besides G-platforms, there are also U-platforms"

That is, RNA can make a "planar" hydrogen-bonded network with four Uracyl bases.
It has been known for a while that such type of tetrads are possible for Guanine, and when various Guanine tetrads stack in top of each other they are called Guanine-Quadruplexes. It seems like the place where this structures occur is the human telomere. The human telomeres are regions of repeated DNA sequence at the end of chromosomes which protect DNA from degradation, their shortening is linked to the process or cellular aging.

The Tokyo University group of Xu, Ishizuka, Kimura, and Komiyama, shows that the U-tetrad stabilizes a G-Quadruplex structure. The results are obtained using NMR, so I don't know if atomic coordinate files are available to play with, if there are, I will post them here for you and I to play with.

Ribosome Controls 2/3 of the Dogma in Bacteria

2010-05-04T09:13:00.000-07:00

In BACTERIA:
transcription speed = translation speed
speed of mRNA making = speed of protein making

Messenger RNA is synthesized by RNA polymerase (RNApol).
In the synthesis process two states can occur, either a forward synthesis state, or a backwards (i.e. backtracking) state making an equilibrium of:

Backwards = Forward

Sergey Proshkin, A. Rachid Rahmouni, Alexander Mironov and Evgeny Nudler show in Science. 2010 Apr 23;328(5977):504-8 that the ribosome shifts equilibrium to forward. They measure the rates of transcription and translation and use molecular tricks to enhance translation. Surprisingly the enhancement of translation induces higher transcription rates.

The second part of this discovery is the molecular component, which comes from Björn M. Burmann,Kristian Schweimer, Xiao Luo, Markus C. Wahl, Barbara L. Stitt, Max E. Gottesman, and Paul Rösch in Science. 2010 Apr 23;328(5977):501-4.
They characterize by NMR a transcription factor (a polymerase protein) called NusG, which, it seems, will bind to a ribosomal protein called NusE, therefore binding RNA polymerase and the ribosome.

With this in mind, it is not clear to me how to interpret the polysome micrographs for the coupled process in bacteria.

My guess is that only the "first" ribosome in the polysome couples to RNA polymerase, the other ribosomes which attach to mRNA in the polysome do not control the coupled rates of transcription-translation, and most likely don't care much about transcription fidelity. I wonder, if you were a protein, and then you were synthesized in that first ribosome, would you be different to your twin copy from the second or the third ribosome in the polysome?

I found this movie for the eukaryotic case:

http://www.ncbi.nlm.nih.gov/books/bookres.fcgi/mcb/ch4anim4.mov

NOTE: One reason why this is only possible in bacteria is that prokaryotes don't have a spliceosome, there is no splicing of pre-mRNA into mature-mRNA as far as I know.

Love python!

2010-04-21T12:14:00.000-07:00

I love python simplicity.

The next code creates a random sequence of RNA of a desired length sooooo easily.


#!/usr/bin/python
import random
import sys

# Print the script usage info if the user
# doesn't supply the correct number of arguments.
if len(sys.argv) != 2: 
        print 'Usage: rnaseq.py ' 
        sys.exit(1)
        
# Read the length of the random RNA sequence
# that you want to generate.
arg1 = sys.argv[1]

# Create the random sequence in the output file
outseq = open('rnaseq%s.seq' % arg1, 'w')
rna = ''.join([random.choice('AUGC') for x in range(int (arg1))])
outseq.write(rna)

The time is ripe for RNA

2010-04-02T14:47:00.000-07:00

Maybe this is one of many posts which insist in the same point, but this time the indicator I'm using is one dear to all U.S.A. based chemists.
Simply, what I want to say is:
In every issue of Chemical and Engineering news there is at least one review per week of a new discovery or advance in RNA understanding, and this has been going on at least for the whole of the last year. Amazing!

This weeks issue mentions a radical mechanism used by enzymes to methylate adenines in the ribosome, and the previous week they talk about the other role of tRNA, that of being an apoptosis (cell-suicide) regulator, and I could go on.

Finally, Sponer's gang has published another article on quantum mechanical calculations of stacked bases. They previously did a study of stacked uracil's, now they are doing a study of stacked adenines. It's interesting to see that they seem not to know the trend on stacking interactions:
purine-purine > pyrimidine-purine > pyrimidine-pyrimidine
They do kind of; "trying to get it out of the way", mention that they are working in vacuo, that the experimental results in vacuo are not comparable, and at the same time they mention that solvation effects are important, explicitly for the B-DNA case, but they seem just to leave it at that.

Perhaps the reason for doing ApA is that someone told them about the NMR and solubility experiments which show the stacking trend?
Also, why don't they use the standard reference frame? It makes it hard to understand their stacked groups and to compare to say RNA geometrical information coming out of curves or 3dna from analysis of x-ray or NMR structures of RNA.

RNA Secondary Structure Drawing

2010-03-26T06:21:00.000-07:00

RNA Secondary Structure drawing can be a very time consuming task, and many times it ends on tediously annotating an existent map using photoshop. Fortunately the people who are involved in developing programs to solve such task are getting better and better, although, for the ribosome, they're not there yet.
To summarize these are the programs and groups which can do the task:

Assemble by Fabrice Jossinet
http://serialized-thoughts.blogspot.com/

VARNA by Kevin Darty, Alain Denise and Yann Ponty
http://varna.lri.fr/index.html

Pseudo-viewer by Y. Byun and K. Han
http://wilab.inha.ac.kr/pseudoviewer

RNAMovies by Uni. Bielefeld group, Robert Giegerich, Dirk J. Evers
http://bibiserv.techfak.uni-bielefeld.de/rnamovies

XRNA by Noller lab.
http://rna.ucsc.edu/rnacenter/xrna/xrna.html

RNAstructure by Mathews/Turner labs.
http://rna.urmc.rochester.edu/RNAstructure.html

What is a non-structured RNA?

2010-03-23T06:26:00.000-07:00

Westhof reviews an article of Weinberg at Breaker's lab (@ Yale) in Genome Biology, 2010, 11, 108.

I can't help but to wonder what non-structured RNA's are, and where one can find them.
Westhof is surprised about the possible emergence of a "whole new" wealth of structured RNA's, but then this makes me wonder what can a non-structured RNA possibly be?, and where are they at?, which shows my need to have a biologist friend. It also makes me wonder about mRNA structure, and why it remains, unstructured, if such is the case, is it due to temperature? Is it due to environment?, I mean, after what temperature are bases not so fond of base-pairing or stacking or, under which environments, meaning, more or less hydrated, closer or not to proteins, etc.

Song Cao, David P. Giedroc and Shi-Jie Chen in RNA 2010 16 538-552.

They extend Flory-Olson, virtual bond idea for RNA, to a new virtual bond between the C4' atom in the sugar, and the N9(N1) atom in the base, to predict loop–helix tertiary structural contacts in RNA pseudoknots, they have a program called V-fold which instantiates the model.
The picture for the, perhaps new (don't know for sure), virtual bond, follows:

J Comput Chem. 2010 Mar 17. Novel graph distance matrix. Randić M, Pisanski T, Novič M, Plavšić D.

And to wrap up these post on new articles for the week, Randic is at it again. He has published a paper which reviews graph distance matrices and proposes a new one which, he claims, can be used to describe 3D graphs of molecules, not just 2D, and in a different way to the D/D matrix which he has previously proposed. The new distance matrix is called ND (Novel Distance), and it's just the Euclidean Distance matrix of the Adjacency matrix of a molecular graph. YES!, that simple.

Weekly Briefing on RNA

2010-03-01T09:22:00.000-08:00

In Zurich they (Erata, Kovacs, Sigel) find that using some type of fancy NMR technique called "(2)J-[(1)H,(15)N]-HSQC (Heteronuclear Single Quantum Coherence) NMR", they can find easier and faster ion bindings to N7 of RNA's Adenine and Guanine, that is, their Hoogsten "face". They use a 27 nucleotide domain 6 of group II Intron to prove their technique.

- J. Am. Chem. Soc., 2010, 132 (11), pp 3668–3669
Jacobs, Resendiz and Greenberg at Johns Hopkins do a direct strand breaking by creating a Uracil radical which then abstracts the C2' hydrogen from the sugar creating a C2' sugar radical which then follows by breakage of the C5' to O5' bond in the backbone. The backbone breakage in aerobic conditions is 1/7 that of the anaerobic case.

Weiss, Zhai, Bhatia and Romaniuk at British Columbia Canada have made an RNA aptamer which binds preferentially to Zinc Fingers (A common protein motif).

More RNA Motifs in the Ribosome

2010-02-17T14:50:00.000-08:00

RNA (2010), 16:375–381

Matthieu G. Gagnon and Sergey V. Steinberg at the Department of Biochemistry of Montreal University report a "new structural motif" in the ribosome they call it: "A-Wedge Motif".

Every once in a while one can't help but to wonder how an article was accepted to a journal. I am not saying that the research is not unique, or that it's not an important discovery, what I'm saying, in this case, is that the new motif is explained in such an utterly confusing way, that I can't really tell what, or where, or how to find this motif. It almost feels as if one was reading a patent, where the wording is kept ambiguous in order to protect industrial secrets. It also seems unfair when you think about your own work or that of your colleagues which have a hard time being accepted for publication when something like this is published, seemingly, so easily.

Nonetheless my stubbornness has made me produce the following two pictures to try and understand what the A-wedge is.

An additional note to mention a new tool for VMD, it's called VDNA (Bioinformatics, 2009, Vol. 25, Pg. 3187), and it allows you to generate nucleosomal DNA structures automatically, and to produce 3DNA parameter output. Thomas Bishop from Tulane University at New Orleans is the author of this neat tool.

RMSD is not the only metric in the world.

2010-01-25T18:26:00.000-08:00

RNA, Vol 15, 1875-1885, 2009
Parisien and Major hit another big methodology "goooool (read it in Spanish)" in the RNA bioinformatics little world.

They propose to use two new quantities, a deformation index, and a deformation profile, to better take into account the local similarity of nucleotides based on the stacking and base-pairing interaction geometry. This in contrast to the more common backbone-centric view, or the all-atom view, which traditionally has stuck to the RMSD metric.

The deformation index is just the ratio of the RMSD to the Mathews Correlation Coefficient. The Deformation Profile is a square matrix whose dimensions are the length of the RNA sequence, and it's values are the average inter-atomic distances between the pyridine ring of bases from a predicted structure with respect to a reference structure.

It has always been interesting to me how Major's group ideas have always felt to me as having a chemical graph theory flavour, which clearly comes from the computer scientist world. For some reason which eludes me, it's still to this day more trendy to approach the RNA bioinfo world from the C.S. side, that the chem. graph theory side. I should try and use this marketing trick myself.

More large RNA's in the horizon.

2009-12-09T08:06:00.000-08:00

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.

Chemical Graph Theory

2009-12-02T11:44:00.000-08:00

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.

Again RNA gets the Nobel Prize!

2009-11-03T15:06:00.000-08:00

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

The first peptide bond. EF-P and Ratcheting

2009-09-21T15:40:00.000-07:00

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

2009-09-10T12:35:00.000-07:00

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

What is an RNA Genome?

2009-08-14T06:42:00.001-07:00

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.

The importance of miRNA

2009-07-27T09:06:00.000-07:00

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

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

2009-07-01T07:32:00.000-07:00

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?

Ribozyme Ligase

2009-06-05T09:00:00.000-07:00

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

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

2009-05-12T14:17:00.000-07:00

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.

Tianbing Xia, David H. Mathews and Douglas H. Turner, RNA, Pergamon Press 2001

2008-05-01T21:53:00.000-07:00

Thermodynamics of RNA Secondary Strucutre Formation

Sequences with identical composition but different permutations of base pairs may have different free energy changes for duplex formation. For example, the duplexes (5'GUUCGAAC3')2 and (5'UUGGCCAA3')2 both have four AU and four GC base pairs, but have free energy changes of duplex formation at 37 C of -8.8 and -11.0 kcal mol-1, respectively. This difference of 2.2 kcal mol-1 translates into a 35-fold difference in equilibrium constants for duplex formation at 37 C. Thus, stability depends on more than the number of hydrogen bonds formed. Presumably, vertical stacking interactions between neighboring base pairs are the sequence-dependent variable.

Wen Tinoco et al. Nature, 452, 598-603, 2008

2008-04-03T21:51:00.000-07:00

DOI: 10.1038/nature06716

Using single molecule spectroscopy Tinoco and collaborators have followed the translation in a single ribosome of and mRNA made up of a 60 bp-hairpin, a GUAA and GUUU tetraloop, and a 49 nucleotide 5' ss region. They have also used a larger mRNA composed of 274 b-p.

Naoko Abe, Hiroshi Abe and Yoshihiro Ito. JACS, 15 November 2007.

2007-11-15T21:50:00.000-08:00

DOI: 10.1021/ja0754453

Ito el al. have synthesized dumbbell RNA's just as had been done before for DNA's by Breslauer et al. (Biochemistry, 1989, 28, 268-273). The utility of this dumbbell RNA's is in RNA interference, they are proven to be more stable to enzymatic degradation and at the same time offer longer RNAi acitivity since the shape does not offer loose ends for enzyme degradation. They have synthesized and compared four different sized dumbbells, that is, Db-15, Db-19, Db-23, Db-27, where the number refers to the size of the double stranded A-type region, the hairloops at the ends of the dumbells are of 9nt size.

Gottesman et al. Science, 26 January 2007

2007-01-01T21:44:00.000-08:00

Taken from C&EN January 22, 2007
Gottesman et al. have found that silent genes are no longer silent. They believe that the resulting proteins will differ in shape due to the different dynamics of their folding. The "silent" genes will act as delayers, and so the final configurational state that proteins with the same aminoacid sequence will fold to, when different synonymous genes are coding for the same aminoacid, will be different.

Moore and Steitz, Tr. in Bioch. Sci. June 2005

2005-09-03T21:43:00.000-07:00

There is still no atomic-resolution structure for a 70S ribosome in any of its states. Consequently, we have no idea why the peptydil-transferase activity of the 70S ribosome is ~10^4 times that of its isolated 50S subunit.

Onoa and Tinoco, Curr. Op. Str. Bio. 2003

2005-09-02T21:42:00.000-07:00

The ultimate application of a better understanding of RNA folding is to predict the folded, partially folded and unfolded states of any RNA in physiological environment.

Chen and Dill, PNAS, 2002

2005-09-01T21:38:00.000-07:00

The principle that emerges, for which there is growing experimental support, is that although protein folding tends to involve highly cooperative two-state thermodynamic transitions, without detectable intermediates, the folding of RNA secondary structures may involve rugged landscapes, often with more complex intermediate states.