The DNA Structure, Part II

James Watson was a young American, who had just completed his PhD. He was interested in protein structure. He moved to Cambridge, England, and began working with Francis Crick, who was a physicist familiar with x-ray crystallography and how to interpret it. The story goes that Watson happened to visit London for a seminar, and saw the x-ray diffraction patterns that Rosalind Franklin had obtained from Maurice Wilkins’ purified DNA. Watson made some notes, rushed back to Cambridge and told Crick what he had seen.

Using Franklin’s data, Watson and Crick were able to deduce a number of key structural elements about how DNA must be shaped. These are things they figured out by looking at those dots on the x-ray crystallograph. First, they learned that the molecule had to form some kind of helix. It had to have a kind of spiral structure, similar to the alpha helix that is characteristic of many parts of proteins. Second, they figured out that the width of this helix was about two nanometers. The interesting thing about this is that, this width was twice the width of what you would have expected if there was only a single helix. That gave them the idea that there had to be more than one helix. A double helix, perhaps.

Another thing they learned was what the regular spacing of the repeated patterning along the length of the molecule is. They saw that there was a repeating pattern at about 0.3 nanometers. This corresponded to the size of one nucleotide. Then there was a larger repeating pattern that was ten times that size. From this they inferred that the number of nucleotides that would occur when the spiral went around just once and returned to the same point in the spiral had to be about ten nucleotides.

That isn’t a lot of information. If I gave you that information you couldn’t tell me the structure of DNA. What Watson and Crick did was to use that data and set out to figure out the structure of DNA the old-fashioned way. They made physical models of the molecule with metal rods. They made large-scale models of DNA several feet tall.

They built many models and asked each time: when we have this model, does it all fit together? They tried over and over again. Eventually they came up with a model that fit. The trickiest part of the modeling was to figure out how the nitrogenous bases fit into the picture. Remember, a polymer of DNA is a repeating pattern of sugars and phosphates, with different nitrogenous bases hanging off the side (the guanines, the adenines and so forth). Where did they fit? If you had two, or even more molecules of DNA that were spiraling together, where do the nitrogenous bases go?

Well, after a couple of failed attempts putting the nitrogenous bases on the outside, Watson and Crick realized they had to go on the inside. Why they might want to put them on the outside? It is the nitrogenous bases that vary along the length of the molecule. It is the variation of the different kinds of nucleotides that must somehow involve the code. If we’re going to get access to that code, we’ve got to make what’s different about that code available to the outside world. They couldn’t get the backbones to work together in any way that made sense with the nitrogenous bases on the outside.

If they turned those nitrogenous bases in, and had the nitrogenous bases connecting with each other, forming kind of stairs, with the backbones of these molecules forming the stringers that are holding the steps; the molecule began to fit together. This actually made sense, because these nitrogenous bases are chemical repelled by water. They want to be on the inside of the molecule because of that.

There was one interesting additional problem. This is actually the most interesting part of the story. That is, how did the bases fit together? If the put the nitrogenous bases on the inside, they could get a double helical structure that began to fit the data, but there was still a problem remaining, there are two kinds of bases, the pyrimidines and the purines, and they are of different sizes. Purines have two rings, and pyrimidines only have one.

If you just try to put these stair steps across the two sides of the double helix, you’ll have some steps that are wider, and some that are narrower. For example, if you got two purines together, you’ll have a relatively narrow step. The outside of this spiral would be going in and out, which is not structurally stable. That’s were Chargaff's rule came in. They realized the implications of Chargaff's rule, which says that the amount of the base adenine (A), always equals the amount of thymine (T). Similarly, the amount of guanine (G), always equals the amount of cytosine (C). This suggested that it may be that one always pairs up with the other when they are matching together on the inside of the helix.

It turns out that when they looked at how these kinds of nitrogenous bases would match up, they found that those peculiar combinations (A and T, C and G) would always maximize that potential weak bonding that occurs between the bases. With this, they actually solved two problems. They figured out how you can have a regular distance along the whole length of the staircase. Also, they figured out what could hold the staircase together. If you always match A with T and G with C, the bonding that holds two sides together is maximized.


In April, 1953, which is only a year after people became convinced that DNA was the information molecule, Watson and Crick published a one-page paper in the journal Nature, which described the double helix. They described the molecular structure and how they thought it would all fit together. The real significance of this work was not simply to describe the 3D structure of DNA, but to show how that 3D structure might actually say something about replication.

Watson and Crick’s paper ends with the following sentence: “It had not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

The fact that A and T, G and C were always paired together, meant that if you took the two sides of the molecule apart, you would always know what the other side has to be. That’s called complementary base-pairing. It was this fact that suggested that mechanism by which DNA was replicated. I’m very excited about this subject, but I will leave it to another article.

The DNA Structure, Part I

After the work of Hershey and Chase, biologists in the early 1950’s became convinced that DNA was what they needed to look at to understand the genetic code. They actually had no idea how DNA could possibly act as a mechanism for genetic inheritance. Let’s step back and remind ourselves of what this molecule has to accomplish. It needs to do two things. First, it needs to have some way of providing a code that can store information about proteins.

The linear structure of DNA, with variable bases along the chain was consistent with the idea that could provide such a code. Proteins also are linear chains. So, you can imagine that there could be some sort of mapping of the pattern of one molecule in the pattern of the other. It wasn’t clear what this mapping could be, but they thought they could figure that out. I will talk about that code in another article.

Second, the molecule had to be able to replicate. If we are going to transmit genetic information, from one generation to the next, it won’t work unless we make duplicate copies of the code, so we can handle one copy of the blueprint to the offspring. The real problem was that it wasn’t clear how DNA could be replicated. The linear structure of DNA offer some hope for a code, but it didn’t offer a clue about how replication might occur.

This is where the race, literally a race, for discovering the three-dimensional structure of DNA began. Scientists were convinced they needed to know the three dimensional structure of DNA to understand replication. It was this impetus that led to the discovery of the now famous DNA double-helix, by Watson and Crick. This was arguably the most important finding in biology in the 20th century.

Why biologists should be interested in the three-dimensional structure of DNA? Biochemists had begun to understand, in the 1950’s, that the function of proteins could be understood by figuring out something about their structure. So, it was hoped that some aspect of the function of DNA, specifically how it was replicated, could be understood by deducing its structure.

What kind of evidence could you use to deduce the three-dimensional structure? The first kind of evidence came from a procedure known as x-ray crystallography. The positions of atoms in a crystal can be inferred from the pattern that they create when you shoot a beam of x-rays through that substance. The x-rays would bend around those atoms, and then, when you look at the pattern on the other side, you see lines and dots in particular orientations and spacing. From them, if you’re familiar with the procedure and very clever, you’ll able to deduce something about the relative positions and orientations of the atoms that make up that structure.

If you shoot an x-ray through a relatively simple crystal, you’ll get a very regular pattern. If you shoot an x-ray through a more complex material, like an organic molecule, you’ll get a much more complex pattern. It is pretty difficult to pull information form that pattern, and infer something about the way the molecule must be structured.

You may be asking, what are we talking about here, crystals or organic molecules? Well, even the most complex organic molecules, in the hands of a good biochemist, can be crystallized. In fact, that’s where the story starts. Maurice Wilkins, a biochemist working at King’s College in London, was able to produce a remarkably pure crystal of DNA. Working with Wilkins was a woman named Rosalind Franklin. She was an expert x-ray crystallographer. She took Wilkins’ purified DNA crystal and was able to get what was to that point the most clear and accurate x-ray crystallograph of DNA that had yet been obtained.

As I said, these patterns are quite hard to interpret. Nowadays we can use computers and algorithms to deduce the structure of proteins from this kind of data, but back then was pretty much painstaking hand calculation and educated guesswork. As it turns out, Wilkins and Franklin puzzled over their x-ray crystallograph trying to deduce something about the structure of DNA. They didn’t quite figure it out. By the time, another person arrived on the scene, James Watson.

Before I introduce Watson, I want to introduce another kind of clue. There was a scientist working at Columbia University named Erwin Chargaff, who discovered a peculiar thing about DNA. He found that if you took the DNA from any organism, and decomposed it into its component nucleotides, you always found a quite interesting relationship. You always found that the amount of the base adenine (A), always equals the amount of thymine (T). Similarly, the amount of guanine (G), always equals the amount of cytosine (C). So, if you take apart the DNA of any organism, you always will find that the amount of A equals the amount T, and the amount of G equals the amount of C.

This was a very curious relationship that became known as Chargaff’s rule. Next time we’re going to talk about James Watson and his codiscovery of the double-helix with Francis Crick.

The Building Blocks of DNA: What Is DNA Made Of?

The building blocks of nucleic acids are called nucleotides. There are only four types of nucleotides. This is one of the reasons why nucleic acids seem relatively simple compared to proteins. Each nucleotide has a sugar that forms a ring. Bonded to one part of this sugar is something called a phosphate group. This phosphate group is just a phosphorus atom with a bunch of oxygen around it. Bonded to another part of the sugar is a nitrogenous base. It is the nitrogenous base that differs from nucleotide to nucleotide. There are four different kinds of nitrogenous bases.

Organic chemists like to number carbons. They actually love carbons because organic chemistry is all about carbons, so they don’t even write them down when they are drawing structures of molecules. If there is a line between two elements, you must assume that there is a carbon there. Instead of writing them, they number the carbons in the sugar around the ring counter-clockwise from one to six. Like this:

There are four kinds of nitrogenous bases. These can be classed into two different groups which differ in size. The pyrimidines have a single six-element ring that’s made of carbons and nitrogens. There are two kinds of pyrimidines, we call them cytosine and thymine. The details aren’t important but these are two kinds of pyrimidines. Here we have drawings of them in order: cytosine and thymine.

The purines, the second kind of nitrogenous bases, are bigger. They are composed of two rings. In addition to the six-element ring that the pyrimidines are made of there is an additional five-element ring that is attached on the side. There are two kinds of purines: adenine and guanine.

We usually refer to the different nucleotides that we find in nucleic acids by the single letter which designates the type of base that it has. We have:

A: adenine.
G: guanine.
C: cytosine.
T: thymine.

Next time we’ll begin to see how this relatively simple polymer, with phosphates and sugars, could serve as a code.