Imperial College London

Henry Rzepa

Science is about making connections. Plenty are on show in Watson and
Crick's famous 1953 article on the structure of
DNA\[cite\]10.1038/171737a0\[/cite\] but often with the tersest of
explanations. Take for example their statement "*Both chains follow
right-handed helices*". Where did that come from? This post will explore
the subtle implications of that remark (and how in one aspect they did
not quite get it right!).

The right handed helix is illustrated in the article cited above as
perhaps the most famous [scientific diagram of the 20th
century](http://www.bbc.co.uk/programmes/b00wltpx){target="_blank"
rel="noopener noreferrer"} (as recounted in the TV program by Marcus du
Sautoy). It was drawn by Odile Crick, a professional artist, and it is
easily her best known work (the original, sadly, appears lost). Many say
it has never been bettered; I do not reproduce it here for fear of
copyright infringement, but you can see Odile (who died only recently)
and her diagram
[here](http://www.lifeinlegacy.com/2007/0707/CrickOdile.jpg){target="_blank"
rel="noopener noreferrer"}. One however has to go to the Watson-Crick
(WC) full paper\[cite\]10.1098/rspa.1954.0101\[/cite\] for an
explanation of why they decided the helix was right-handed, or (P)- in
CIP terminology.\[cite\]10.1002/anie.196603851\[/cite\] In my opinion
(as a chemist), this is a far better read than the short and more famous
note in Nature. There (on page 87) one finds the immortal statement "*we
find by trial and error that the model can only be built in a
right-handed sense"*. They follow that remark with another which I will
quote later in this post. But the preceding observation is footnoted,
and that footnote must rank as one of the most unheralded in science
(unlike *e.g.* Fermat's). For this footnote notes another article,
published just two years earlier\[cite\]10.1038/168271a0\[/cite\] in
which the absolute handedness of a small molecule was finally confirmed
after \~50 years. The molecule is shown below, and again in modern CIP
terminology, the two chiral carbon atoms both have (R) configurations
rather than (S). Until this point, the (R) configuration had merely been
a guess with an evens chance of it being right (and had it been wrong,
imagine how many textbook diagrams would have needed changing!).

::: {#attachment_3243 .wp-caption .aligncenter style="width: 168px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/tartrate.jpg "tartrate"){.size-full
.wp-image-3243 loading="lazy" decoding="async"
aria-describedby="caption-attachment-3243" width="158" height="208"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/tartrate.jpg 315w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/tartrate-227x300.jpg 227w"
sizes="(max-width: 158px) 100vw, 158px"}](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/tartrate.jpg)

The absolute configuration of natural tartaric acid.
:::

Chemists had, in the preceding 50 years, by synthesis and
transformation, connected the configuration of tartrate to the ribose
sugars that form the linker in DNA, and so Watson and Crick built their
famous model of DNA assured in the knowledge that the **absolute
configuration** of their ribose sugar was correct. But that assurance,
it is important to remember, had only come two years earlier! The
(correct) structure of DNA was very much a discovery of its time, and
this connection between tartrate and DNA I think deserves the accolade
of *great connections in science* (I write this in the Semantic Web
sense)*.*

On to another statement to be found in the full WC article: "*Left
handed helices can only be constructed by violating the permissible van
der Waals contacts*" Given the nature of the molecular model building
tools that WC\[cite\]10.1039/JR9480000340\[/cite\] had at their
disposal,^\*^ I suspect we must forgive them this
assertion.\[cite\]10.1016/0022-2836(79)90506-0\[/cite\],\[cite\]10.1038/287755a0\[/cite\]
But of course, building models using the [van der
Waals](http://en.wikipedia.org/wiki/Van_der_Waals_force){target="_blank"
rel="noopener noreferrer"} constraints (amongst others of course) is
what modern computers are really very good at. So what might a modern
visitation of this very issue yield? Shown below is a small DNA duplex,
named d(CGCG)~2~ (DOI:
[10.2210/pdb1zna/pdb](http://dx.doi.org/10.2210/pdb1zna/pdb)) This uses
only the CG base-pairing motif (the other of course is AT). Well, it
turns out that DNA constructed from CG-rich duplexes does NOT
necessarily adopt a right handed helix after all! WC (for this
particular condition) were in fact wrong, and clearly the van der Waals
contacts are not after all objectionable. Left-handed helices (as a left
hander myself, I am naturally drawn to them) are also known as Z-DNA
(the right handed form is called B-DNA), although many left-handed
representations have in fact been [drawn in
error](http://users.fred.net/tds/leftdna/Leftwhole.html){target="_blank"
rel="noopener noreferrer"}.

::: {#attachment_3247 .wp-caption .aligncenter style="width: 312px"}
  
![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/1ZNA.jpg "1ZNA"){.size-full
.wp-image-3247 loading="lazy" decoding="async"
aria-describedby="caption-attachment-3247"
onclick="jmolInitialize('../Jmol/',true);jmolSetAppletColor('yellow');jmolApplet([500,500],'load wp-content/uploads/2010/12/1ZNA-H.mol2;set measurementUnits Angstroms;measure 90 198;measure 91 249;measure 74 248;measure 112 246;measure 53 245;measure 52 218;measure 33 226;measure 131 243;measure 132 250;measure 11 238;measure 12 241;measure 153 240;measure 183 173;measure 181 189;measure 178 184;measure 64 181;measure 221 229;measure 223 213;measure 188 175;measure 202 210;spin 3;');"
width="302" height="266"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/1ZNA.jpg 604w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2010/12/1ZNA-300x264.jpg 300w"
sizes="(max-width: 302px) 100vw, 302px"}

The DNA duplex d(CGCG) showing a left handed helix. The ribose is in the
2E conformation. Click for 3D and see if you can find any objectionable
van der Waals contacts!
:::

The model when stripped of its water molecules, is then of a size (250
atoms) which is easily amenable to a modern quantum-mechanical DFT
calculation. Importantly, this has to include dispersion corrections
(the van der Waals contacts referred to above) to get the correct
geometry, and one can use *e.g.* ωB97XD/6-31G(d) + continuum water
solvation correction to compensate for the missing
waters\[cite\]10.1039/C0CC04023A\[/cite\] for an example of its use for
a large molecule, or indeed [this
post](http://www.ch.ic.ac.uk/rzepa/blog/?p=2594){target="_blank"
rel="noopener noreferrer"}). In truth, this combination of
characteristics in a model has only recently become possible for a
molecule of such size.

Well, now that a good accuracy wavefunction for *e.g.* d(CGCG) is
possible, what might one do with it? Well, the chiro-optical properties
might be calculated\[cite\]10.1002/chir.20804\[/cite\] including the
[optical rotation at a specified
frequency](http://www.ch.ic.ac.uk/rzepa/blog/?p=3326){target="_blank"
rel="noopener noreferrer"}, or *e.g.* the electronic circular dichroism
spectrum. Such properties are normally computed only for much smaller
molecules. Watch this space (or the journals).

------------------------------------------------------------------------

^\*^ Note added in proof (as the saying goes): This
article\[cite\]10.1039/JR9480000340\[/cite\] by Derek Barton published
in 1947, some six years before WC claimed "*violation of  the
permissible van der Waals contacts*", established clearly the principles
behind the model building by WC and in many ways could be described as
the start of quantitative molecular model building. The very same
equation used by Barton to model dispersion attractions is still used in
*e.g.* the ωB97XD DFT method noted above.

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


Science is about making connections. Plenty are on show in Watson and Crick’s famous 1953 article on the structure of DNA[cite]10.1038/171737a0[/cite] but often with the tersest of explanations. Take for example their statement “
<em>
 Both chains follow right-handed helices
</em>
”. Where did that come from?

Messaggi di Rogue Scholar

The handedness of DNA: an unheralded connection.