Download Review of "A proposed structure for the nucleic acids" by Pauling

Review of "A proposed structure for the nucleic acids" by Pauling and Corey
Pauling and Corey have proposed a precise atomic structure for nucleic acid polymers. As the
authors clearly state, the proposed model is partially consistent with x-ray diffraction data, but should
still be considered just a proposal and not accepted as correct. The authors succinctly summarize the
sum of the chemical knowledge of the chemical structure of DNA. That is, the repeating unit if DNA is
composed of a deoxyribose sugar linked via carbon 1 to a purine or pyrimidine base and linked via the
3' and 5' hydroxyls to adjacent units throughout a phosphate ester.
As the authors describe, it has been challenging to acquire high quality x-ray diffraction data for
standard nucleic acid preparations such as sodium thymonucleate from calf thymus. Oddly, the
authors comment on the poor quality of their own photographs, and so rely heavily on the photographs
of Astbury and Bell.
The first assumption of this work is that polynucleotides will be helical. I find the reasoning here
be quite odd, since the authors are arguing that the structure of the alpha-helix provides some sort
precedent. I don't see any reason why the two should necessarily be connected. If the authors wish
keep this discussion in the paper, I think they should present the electron micrograph evidence
support of this conclusion first, and then draw the comparison with the alpha-helix only later.
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Based on a 'back of the envelope' type calculation, the authors estimate that the length per residue
is 1.1 angstrom (an error estimate would be appropriate for this number). Since this value is less than
the van der Waals radius of both carbon and phosphorus, the authors suggest that each unit must be
composed of multiple residues. For consistency with a strong reflection with a spacing of 3.4
angstrom, the authors propose that there are likely 3 residues per unit. Given the fundamental
importance of this question (#residue per unit), I think that an error estimate on the length per residue
estimate would be very appropriate. That is, if this number was just 0.4 angstroms less the logical
conclusion would be that there are 4 residues per unit, and if this number was 0.6 angstroms larger,
one would assume 2 residues per unit.
The authors go on to propose a well-packed 3-chain coiled structure. The authors consider 3
possibilities for the group that is packed closest to the core: the phosphates, the sugars, or the bases.
The authors dismiss the possibility of packing the sugars or the bases near the core for reasons that
are not well explained. I feel that it would be important to discuss the geometries that were considered
and the problems that were found.
The preferred model proposed by the authors has the phosphates packed near the core of the
helix. The authors find that the phosphates in this model can be linked by the ribose moieties, but that
there remain steric clashes and a distortion of the phosphate groups that would render this a fairly
high energy conformation. It certainly does not seem to be the sort of elegant structure that one would
expect for the fundamental building block of life. Would such a structure be expected to form
spontaneously? Particularly troubling for me is the fact that the phosphates are inaccessible to
divalent cations, and one would expect that divalent cations would actually inhibit the formation of this
structure. I believe this prediction is at odds with the known before of sodium thymonucleate.
One nice feature of this model is that, by positioning the bases on the outside of the helix, it does
provide a clear mechanism by which proteins could recognize specific sequences of DNA. If the bases
were directed towards the inside, it is less clear how this recognition could be achieved.
Overall, I find this proposed structure to be intriguing and thought-provoking. However, there are
clearly several fundamental problems with this model that suggest to me that it is unlikely to be the
correct structure of DNA. My recommendation is that the this manuscript be accepted after minor
revisions. Specifically I would like them to address the comments included in the text above, and also
add a concluding paragraph in which both the strengths and weaknesses of their model are clearly
spelled out. The inclusion of such a summary paragraph will allow readers, expert and non-expert
alike, to better place this model in the proper context. In this way, it make act to stimulate others to
propose better models and finally answer the most fundamental question in biology.