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Non-canonical Base Pairs show Watson-Crick pairing in MD simulations

Elucidating the pairing of non-hydrogen bonded unnatural base pairs (UBPs) is still a controversial subject due to the lack of specificity in their mutual interactions. Experimentally, NMR is the method of choice but the DNA strand must be affixed on template of sorts such as a polymerase protein. Those discrepancies are well documented in a recent review which cites our previous computational work, both DFT and MD, on UBPs.

Since that last paper of ours on synthetic DNA, my good friend Dr. Rodrigo Galindo from Utah U. and I have had serious doubts on the real pairing fashion exhibited by Romesberg’s famous hydrophobic nucleotides d5SICS – dNaM. While the authors claim a stacked pairing (within the context of the strand in the KlenTaq polymerase enzime), our simulations showed a Watson-Crick-like pairing was favored in the native form. To further shed light on the matter we performed converged micro-seconds long simulations, varying the force field (two recent AMBER fields were explored: Bsc1 and OL15), the water model (TIP3P and OPC), and the ionic compensation scheme (Na+/Cl or Mg2+/Cl).

In the image below it can be observed how the pairing is consistently WC (dC1′-C1′ ~10.4 A) in the most populated clusters regardless of the force field.

Also, a flipping experiment was performed where both nucleotides were placed 180.0° outwards and the system was left to converge inwards to explore a ‘de novo’ pairing guided solely by their mutual interactions and the template formed by the rest of the strand. Distance population for C1′ – C1′ were 10.4 A for Bsc1 (regardless of ionic compensation) and 9.8 A for OL15 (10.4 A where Mg2+ was used as charge compensation).

This study is now published in the Journal of Biomolecular Structure & Dynamics

Despite the successful rate of replication by a living organism -which is a fantastic feat!- of these two nucleotides, there is little chance they can be used for real coding applications (biological or otherwise) due to the lack of structural control of the double helix. The work of Romesberg is impressive, make no mistake about it, but my money isn’t on hydrophobic unnatural nucleotides for information applications 🙂

All credit and glory is due to the amazing Dr. Rodrigo Galindo-Murillo from the University of Utah were he works as a developer for the AMBER code among many other things. Go check his impressive record!


#RealTimeChem – Happy birthday DNA!

What a happy coincidence -if indeed it was- that #RealTimeChem week happened to coincide with the sixtieth anniversary of the three seminal papers published in Nature on this day back in 1953, one of which was co-authored by J. Watson and F. Crick; of course I mean the publication for the first time of the structure of deoxyribose nucleic acid, or DNA, as we now call it.

You can get the original Nature papers from 1953 here at: (costs may apply)

Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid 737


Molecular Structure of Nucleic Acids: Molecular Structure of Deoxypentose Nucleic Acids 738

Molecular Configuration in Sodium Thymonucleate 740

Nature’s podcast released two episodes (called ‘pastcast’) to celebrate DNA’s structure’s birthday, one of them is an interview with Dr. Raymond Gosling who in 1953 worked under Dr. Rosalind Franklin at King’s College London in diffractometry of biological molecules. If you haven’t listened to them you can get them here at Of course, the history around the discovery of DNA’s structure is not without controversy and it has been long argued that the work of Franklin and Gossling didn’t get all deserved credit from Watson and Crick. In their paper W&C acknowledge the contribution of the general nature of DNA from the unpublished results by Franklin’s laboratory but that is as far as they went, they didn’t even mention photo 51 which Crick saw at Wilkins laboratory, who in turn got it from Gossling at Franklin’s suggestion. Still, no one can deny that the helical structure with which we are now familiar is their work, and more importantly the discovery of the specific pairing, which according to Gossling was a stroke of genious that probably couldn’t have happened in his own group, but without Franklin’s diffraction and Gossling’s crystallization  there was little they could do. Details about the process used to crystallize DNA can be heard in the aforementioned podcast, along with an inspiring tale of hard work by Dr. Gossling. Go now and listen to it, its truly inspiring.

For me it was not the story of a helix, that I was familiar with; it was the story of the specific pairing of two hélices
– Dr. Raymond Gosling

Famous Photo 51 by Dr. Rosalind Franklin and Raymond Gosling (Source: Wikipedia)

The iconic Photo 51 by Dr. Rosalind Franklin and Raymond Gosling (Source: Wikipedia)

Above, the iconic Photo 51 taken by Franklin and Gossling (have you ever noticed how most scientists refer to Franklin just as Rosalind but no one refers to Watson as James? Gender bias has a role in this tale too) To a trained crystallographer, the helical symmetry is evident from the diffraction pattern but going from Photo 51 to the representation below was the subject of hard work too.

Modern DNA representation (Source: Wikipedia)

Modern DNA representation (Source: Wikipedia)

There are million of pages written during the last 60 years about DNA’s structure and its role in the chemistry of life; the nature of the pairing and the selectivity of base pairs through hydrogen bond interactions, an interaction found ubiquitously in nature; water itself is a liquid due to the intermolecular hydrogen-bonds, which reminds us about the delicate balance of forces in biochemistry making life a delicate matter. But I digress. Millions of pages have been written and I’m no position of adding a meaningful sentence to them; however, it is a fascinating tale that has shaped the course of mankind, just think of the Human Genome Project and all the possibilities both positive and negative! DNA and its discovery tale will continue to amaze us and inspire us, just like in 2011 it inspired the Genetech company to set a Guiness World Record with the largest human DNA helix.

Genetech SF, Cal. USA (Source

Genetech SF, Cal. USA (Source

Happy birthday, DNA!

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