So the Hershey-Chase experiment in 1952 gave us really strong evidence that DNA is containing our genetic material and is the molecule that is inherited. At the same time in the early 1950s, there are a few groups of scientists who are working on better understanding the three-dimensional structure of DNA, because by understanding the structure of DNA, we can better make hypotheses about how that DNA functions, how it is replicated. and how it is inherited. So that's what we're going to focus on here, is that three-dimensional structure. This is a bit of a review, but as a reminder, our nucleic acids, like DNA, are polymers, and they are made up of monomers, and the monomers are nucleotides.
The nucleotides have three main components. There are phosphate groups, There is a five-sided sugar. In this case with DNA, we're talking about deoxyribose is our sugar.
If it was RNA, it would be ribose. But focus on DNA, deoxyribose is our sugar. And then a nitrogenous base. And those bases are categorized into either pyrimidines or purines.
The purines have two rings. The pyrimidines have one ring. For DNA, you have adenine and guanine and cytosine and thymine.
For RNA, instead of thymine, it gets replaced with uracil. But other than that, very similar. So we understood the structure of a nucleic acid at this point already, but learning how to piece these nucleic acids together in a three-dimensional shape, like a molecule, was...
really perplexing for scientists. And this was the focus of a lot of research in this area, was how do we connect these pieces together, these monomers together, to create a larger structure? What does that structure look like based on what we know about the biochemistry of these smaller molecules? So I'm not going to get into the whole story here, but I am going to just highlight a couple of main characters.
in this kind of road to the discovery of this three-dimensional structure. I already mentioned Francis Crick and James Watson, who are the two that historically have been mainly credited with putting forward the first accurate three-dimensional model of DNA. Those two, along with a guy named Maurice Wilkins, all won the Nobel Prize for this discovery.
Someone you may have heard of, heard of is Rosalind Franklin. She was a scientist who worked in the same lab as Wilkins and did a lot of the experiments that were necessary to kind of confirm the hypothesis or the model that was put forth by Watson and Crick. And historically, she's been sort of underrepresented.
More recently, she's gotten kind of more respect for her contributions. So that's why maybe you have heard of her. But she was not part of this group that won the Nobel Prize, despite her really major contributions.
And there are a lot of different reasons for that that we'll get into in class. Another guy's name who you may have not heard of is Raymond Gosling. He is... a scientist who he was a phd student working with rosalind franklin uh and then later with wilkins um erwin shargov shargov who we talked about early in the semester shargov's um complementary base pairing rules huge contribution to watson and crick's model and then linus pawling is a guy who didn't um make any huge contributions in terms of understanding the 3d model uh but was you kind of the main competitor of Wilkins and Franklin and Watson and Crick in terms of kind of racing them to understand or put forth the first accurate model for what DNA looked like.
And so in class, I'll get into a little more detail on kind of each of these characters, for lack of a better term, and kind of what they did, what they didn't do, what have they been credited for and like how they're. contributions have like, you know, changed history and our understanding of science. It's a really, really cool, fascinating look at. both science but also bioethics and just like the the the personality of all of these really huge names in this area of molecular biology. So the very abridged version of the story is that Watson and Crick in 1953 published their their knowledge of or their their model of DNA.
What's kind of interesting about this is Watson and Crick didn't actually do any experiments. They instead just combined knowledge from experiments done by people like Rosalind Franklin and Ervin Chargoff and others, and also their general knowledge of biochemistry and molecular biology to piece together a model that made sense. So two of the biggest contributors to or not necessarily contributors to, but two of the biggest, like the foundation for this model that Watson and Crick put forth are mainly on, first, Shargoff. His discovery that adenine and thymine were always present in equal amounts and guanine and cytosine were always present in equal amounts led to the idea that of complementary bases and was the kind of first major evidence for Watson and Crick to say, hey, maybe these bases point to the inside as opposed to the outside.
And then x-ray crystallography, basically like x-ray images of molecules performed by Rosalind Franklin and Raymond Gosling, showed that the overall structure of DNA must be helical. nature or like a spiral shape and very famously there's one x-ray crystallography is a really difficult technique to master and Rosalind Franklin and Raymond Gosling dedicated their time to mastering just that and a very famous image that they took called photograph 51 here was the main evidence that this DNA is helical this image is it's tough to appreciate if you don't understand x-ray crystallography, which I'm not going to ask you to understand it. But this image is very, very like crystal clear, very, very high resolution for the technology they had at the time and went a huge way in demonstrating that the overall three-dimensional shape of DNA was helical. And although Franklin and Gosling obtained this image, it was shown to uh watson and crick who then use that to confirm and say hey we have a helical model and then plus that with erwin shargoff's discovery um the bases face in that and a few other things they were able to piece together their model which we'll talk about on the next slide so first how are the individual bases linked well this is something that we've already talked about so the the nucleotides form phosphodiester bonds uh in a five prime to three prime direction the five prime carbate five prime carbon on top and the three prime carbon on bottom so for a single strand of dna there are phosphodiester bonds between the sugars and phosphates the five prime carbons form a bond with the phosphate which is attached to the three prime carbon of the nucleotide ahead of that and whenever we add a new nucleotide we're adding it to the three prime end we're going five prime to three prime so this is one strand and then the opposite strand is matching it but going the other direction instead of five prime up here three prime up here the opposite strand would be three prime up here and five prime up here so this was you know one step in understanding right that concept of anti-parallel and then how the bases kind of connect on not the bases but the nucleotides connect on the what would be the rungs of the ladder So we have that individual strand held together by the phosphodiester bonds, and then the complementary strand is anti-parallel, right? Here it's a little flipped, but 3'here, 5'here, 5'here, 3'here.
So we have two individual strands. How are those individual strands connected? Well, because of Chagroth's rule, and we knew that the bases must have faced in and bound to each other. So those hydrogen bonds that connect the bases between adenine and thymine and cytosine and guanine.
are formed here. So complementary to base pairing, right, Shargoff's contributions led to this, this hydrogen bonding, because whenever we had an A, we had a T, and vice versa. Whenever we had a G, we had a C, and vice versa. So that's why they're always present in equal amounts. Two strands are anti-parallel, three prime to five prime, five prime to three prime.
This was kind of pieced together by, correct me if I'm wrong, and Watson's knowledge of biochemistry. It was the only way that it made sense that it fit. And then due to Rosalind Franklin and Raymond Gosling's work, they understood that this ladder that was formed must be twisted and turned in some way to form this helical shape and that the helical shape is very uniform.
So that's how we arrive at this double helix structure, this twisted ladder, which is... completely uniform right every turn right from this point to this point of the helix is exactly 3.4 nanometers and the helix width throughout the whole thing is 2 nanometers and this is true throughout the whole strand of DNA so it's kind of these four properties that Watson and Crick were able to put together to present this model, which turned out to be very, very accurate. And yeah, so since this, and it wasn't as if, you know, Watson and Crick put this out, and all of a sudden, everyone agreed with them. They faced a lot of controversy, and there were still detractors, you know, even decades later, and late into the late 1960s and 1970s.
But ultimately it was this model that was correct and understanding this model led to our understanding of how DNA functions, in other words, how DNA replicates, which we'll talk about in the next recording.