Thursday, July 26, 2007

The Watson & Crick Nature Paper (1953)

Watson & Crick submitted their paper on the structure of DNA to the journal Nature on April 2, 1953. It was published in the April 25th issue—a remarkably rapid publication even for that time. A PDF of the paper as it appeared in the journal is here. The original typed manuscript is here.

Now that we've learned about the structure of DNA and it's history [Theme: DNA] we're in a position to work through this seminal paper line-by-line. Let's begin with the title and the opening sentence.
A Structure for Deoxyribose Nucleic Acid

We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.
The name of this important molecule is now deoxyribonucleic acid but in 1953 there was no standard nomenclature so Watson & Crick used a common name.

The first sentence is a classic understatement and you can be sure that it's written by Crick and not Watson.
A structure for nucleic acid has already been proposed by Pauling and Corey1. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons:

(1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other.

(2) Some of the van der Waals distances appear to be too small.
At the time they wrote the paper, Pauling had not seen their model so Watson & Crick were not certain that he would agree with them. (See Linus Pauling's notes taken during the meeting with Watson & Crick on April 8, 1953.) They were obliged to insert some commentary about competing ideas concerning the structure of DNA, especially the Pauling & Cory model that had just been published several weeks earlier in the Proceedings of the National Academy of Sciences (USA) [Pauling & Cory, 1953]. (The three-stranded structure of DNA from the Pauling & Cory paper is shown above.)

No doubt Watson & Crick were delighted to be able to correct the famous Linus Pauling. The idea that Pauling might have got the structure wrong because of simple mistakes like packing charged molecules together and not allowing for proper van der Waals distances was too tempting to omit.
Another three-chain structure has also been suggested by Fraser (in the press). In his model the phosphates are on the outside and the bases on the inside, linked together by hydrogen bonds. This structure as described is rather ill-defined, and for this reason we shall not comment on it.
Bruce Fraser published a brief note where he took issue with the Pauling & Cory paper but, as Watson and Crick note, the proposed structure is not described in any detail. There are no figures. The Fraser manuscript is here].
We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid. This structure has two helical chains each coiled round the same axis (see diagram). We have made the usual chemical assumptions, namely, that each chain consists of phosphate diester groups joining beta-D-deoxyribofuranose residues with 3',5' linkages. The two chains (but not their bases) are related by a dyad perpendicular to the fibre axis. Both chains follow right-handed helices, but owing to the dyad the sequences of the atoms in the two chains run in opposite directions. Each chain loosely resembles Furberg's2 model No. 1; that is, the bases are on the inside of the helix and the phosphates on the outside. The configuration of the sugar and the atoms near it is close to Furberg's "standard configuration," the sugar being roughly perpendicular to the attached base. There is a residue on each every 3.4 A. in the z-direction. We have assumed an angle of 36° between adjacent residues in the same chain, so that the structure repeats after 10 residues on each chain, that is, after 34 A. The distance of a phosphorus atom from the fibre axis is 10 A. As the phosphates are on the outside, cations have easy access to them.
Everything important about the structure of DNA is contained in this paragraph except for the base pairs. Note how important it was to confirm that the nucleotide conformation is similar to that which Furberg saw in the structure of cytidylate.

The important points about the backbone chains are that there are only two of them, that they form a regular helix, and the chains run in opposite directions. Recall that it was Crick who recognized the the chains had to be anti-parallel and nobody else, including Franklin and Wilkins, had thought of this.
The structure is an open one, and its water content is rather high. At lower water contents we would expect the bases to tilt so that the structure could become more compact.
This is an oblique reference to the A form of DNA that Rosalind Franklin was working on. The A form is somewhat dehydrated and the helix is more compact. Just as Watson & Crick predict, the bases are tilted in the A form.
The novel feature of the structure is the manner in which the two chains are held together by the purine and pyrimidine bases. The planes of the bases are perpendicular to the fibre axis. They are joined together in pairs, a single base from one chain being hydroden-bonded to a single base from the other chain, so that the two lie side by side with identical z-coordinates. One of the pair must be a purine and the other a pyrimidine for bonding to occur. The hydrogen bonds are made as follows: purine position 1 to pyrimidine position 1; purine position 6 to pyrimidine position.

If it is assumed that the bases only occur in the structure in the most plausible tautomeric forms (that is, with the keto rather than the enol configurations) it is found that only specific pairs of bases can bond together. These pairs are: adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine).
The pairing of A with T and G with C to form base pairs in the middle of the helix is the most important part of the proposed structure. It could not have been determined from the X-ray diffraction data. It could only be deduced by model building. Note that Watson & Crick emphasize the correct tautomeric forms of the bases since most of the textbooks of the day showed the incorrect forms.
In other words, if an adenine forms one member of a pair, on either chain, then on these assumptions the other member must be thymine; similarly for guanine and cytosine. The sequence of bases on a single chain does not appear to be restricted in any way. However, if only specific pairs of bases can be formed, it follows that if the sequence of bases on one chain is given, then the sequence on the other chain is automatically determined.
This is the idea of complementarity that was very much in the air among the insiders. It's an entirely theoretical idea but the fact that the structure conformed made it all that much more elegant a solution. The "beauty" of the structure derives in large part from the fact that it explains so much.
It has been found experimentally3,4 that the ratio of the amounts of adenine to thymine, and the ratio of guanine to cytosine, are always very close to unity for deoxyribose nucleic acid.
This is a reference to the Chargaff ratios.
It is probably impossible to build this structure with a ribose sugar in place of the deoxyribose, as the extra oxygen atom would make too close a van der Waals contact.
An insight that proved to be correct. The Watson & Crick structure explains one more thing that none of the other structures could explain.
The previously published X-ray data5,6 on deoxyribose nucleic acid are insufficient for a rigorous test of our structure. So far as we can tell, it is roughly compatible with the experimental data, but it must be regarded as unproved until it has been checked against more exact results. Some of these are given in the following communications. We were not aware of the details of the results presented there when we devised our structure, which rests mainly though not entirely on published experimental data and stereochemical arguments.
Watson & Crick know full well that their structure is compatible with published data from Astbury (ref. 5) and Wilkins & Randall (ref. 6). They also know that some of the key features of their model, such as base pairing, cannot be verified by X-ray crystallographic data from DNA fibers fibres.

They make reference to the accompanying papers by Franklin & Gosling and by Wilkins, Stokes, and Wilson ("following communications"). This was a standard way of referring to papers that were in press but Watson & Crick have been criticized for not mentioning the authors by name, especially Rosalind Franklin and Maurice Wilkins.

The last sentence has been widely interpreted as somewhat disingenuous. Of course they were aware of the results, including many of the details that had not been published (see below). A great deal of the structure of the backbones was informed by the results from Franklin's unpublished X-ray images of B-DNA. It would have been much better if Watson & Crick had stated here—as a personal communication—that they had received information from Wilkins and Franklin.
It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.
Another very famous sentence from the paper and another classic example of understatement. Watson & Crick follow up on this with another Nature paper that describes how DNA replication should work. The fact that an obvious mechanism of replicating DNA is apparent from looking at the structure is another example of its beauty and elegance. These were the sorts of thing that made the structure so appealing to those who were working on these problems. On the other hand, they meant nothing to most biologists, many of whom were not inclined to believe the Watson & Crick structure when it was first published. Remember that for most biologists this was the first time they were confronted with the idea that DNA was important. Watson & Crick had know for years that DNA was the secret of life but the rest of the world still thought DNA was unimportant.
Full details of the structure, including the conditions assumed in building it, together with a set of coordinates for the atoms, will be published elsewhere
The "details" were published in The Proceeding of the Royal Society in January, 1954.
We are much indebted to Dr. Jerry Donohue for constant advice and criticism, especially on interatomic distances. We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King’s College, London. One of us (J. D. W.) has been aided by a fellowship from the National Foundation for Infantile Paralysis.
One of the myths that has grown up about the discovery of the double helix is that Watson & Crick never acknowledged Franklin and Wilkins. This myth is due, in part, to the fact that Wilkins and Franklin are not mentioned in the body of the paper where it would have been appropriate (see above). However, they are clearly mentioned in the acknowledgments even though the reference seems to contradict their earlier statement about being unaware of unpublished results.

9 comments:

  1. The last part of the DNA series, but this post in particular, successfully confer the sense of beauty, excitement and awe when a model "clicks" in place which I recognize well (albeit in much smaller contexts). Again, well done!

    Btw, it seems to be an excellent example of the common observation that the most elegant (expressive) models must rely on simplicity - the three stranded models came up short. Old Occam was on to something valuable.

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  2. The famous drawing of the double helix in that Nature paper was made by Francis Crick’s wife Odile who was a talented artist and who died earlier this month.

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  3. Thanks for the DNA series. Great stuff.

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  4. uhm..knowing this stuff about DNA is very awesome, hmm..how about its labels?

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  5. That is highly intriguing what you are writing.
    The problem is still unsolved by Watson and Crick: what makes complementary nucleotides rotate in space producing a DNA spiral?

    Alex Tulub
    Liverpool uni

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  6. Where can i find the original typed manuscript?

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    1. Je recherche moi aussi le lien vers le manuscrit original.
      Merci pour vos indications.
      Eric

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  7. I didn't know they published the "photograph 51" in their article. It was interesting.

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