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DNA AS THE GENETIC MATERIAL

DNA discovery and

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Discovery of the structure of DNA

Introduction
When you think about the discovery of DNA, the famous duo of James Watson
and Francis Crick may immediately come to mind. But were Watson and Crick the
original discoverers of DNA?

Molecular structure of DNA

Antiparallel structure of DNA

strands

Classic experiments: DNA as

Although these two played a crucial role in solving DNAs three-dimensional

structure, the molecule itself was first discovered nearly 100 years earlier by a
biologist named Friedrich Miescher. Meischer was studying proteins in human
white blood cells (which he, rather disgustingly, harvested from pus-covered
bandages) when he isolated a new, phosphorous-rich substance that did not
behave like a protein. Miescher named this compound nuclein, for its location in
the nucleus1 .

the genetic material

Discovery of the structure of

Although nuclein was, in fact, what we now call DNA, Meischer had no idea of its
purpose, and its key role in heredity would remain a mystery until the middle of the
20th century.

DNA

Nucleic acids

NEXT SECTION:
DNA replication

Setting the stage

In the first half of the 20th century, the scientific community largely viewed DNA as
a boring and unimportant polymer, a poor candidate for carrying hereditary
information. Instead, most researchers thought that protein would prove to be the
heritable molecule, thanks to its more variable composition and high abundance in
cells. However, as experimental evidence poured in from Avery, Hershey and
Chase, and others, researchers began to gradually accept that DNA might indeed
carry hereditary information. At that point, the question became: how?
From the work of Russian-born American biochemist Phoebus Levene and others,
scientists knew that DNA was composed of subunits called nucleotides, which
were themselves made up of three parts: a sugar (deoxyribose), a phosphate
group, and one of four nitrogenous bases (adenine (A), thymine (T), guanine (G)
and cytosine (C); see figure below)1 . C and T bases, which had just one ring, were
classified as pyrimidines, while A and G bases had two rings and were called
purines. DNA nucleotides were known to assemble in chains linked by
phosphodiester bonds, which formed between the deoxyribose sugar of one
nucleotide and the phosphate group of the next. This arrangement created an
alternating chain of deoxyribose sugar and phosphate groups in the DNA polymer,
a structure known as the sugar-phosphate backbone. Attached to the sugarphosphate backbone were the nitrogenous bases of the individual nucleotides.

Image credits: left panel, image modified from "Nucleic acids: Figure 1," by
OpenStax College, Biology (CC BY 3.0). Right panel, image modified from "DNA
chemical structure," by Madeleine Price Ball (CC0/public domain).
Despite their understanding of the basic anatomy of a DNA strand, researchers at
the time did not know how many nucleotide strands made up a DNA molecule,
how those strands were arranged in space, or, most critically, how the structure of
DNA might allow hereditary information to be encoded and transmitted.

Chargaff and his rules

The Austrian biochemist Erwin Chargaff was among the first to embrace the idea
of DNA as the genetic material. Spurred on by Averys findings, he started to
investigate how DNA might carry hereditary information.
Chargaff isolated DNA from a variety of species and analyzed its base
composition, looking to see if there were any differences among them. Many
scientists of Chargaffs time would have predicted the answer to be no, thanks to
an influential idea called the tetranucleotide hypothesis, proposed by Phoebus
Levene. The tetranucleotide hypothesis proposed that all DNA molecules were
made up of equal proportions of the four nucleotides (that is, nucleotides with A, T,
C and G bases), and that these nucleotides were arranged in identical, repeating
units1 . This idea, which suggested that DNA molecules did not vary in composition
and were thus poorly suited to carry information, kept many scientists from
accepting DNA as the genetic material.
Chargaffs findings provided strong evidence against the tetranucleotide
hypothesis. Specifically, he found that:
The proportions of the four DNA bases varied from species to species, but
were the same between different tissues of a single species. I.e., the DNA of
a starfish would have a different proportion of adenine than the DNA of a
human, but DNA from human blood would have the same composition as
DNA from human skin.

 In every species, the abundance of adenine roughly equaled that of thymine

(A = T), and the abundance of guanine roughly equaled that of cytosine (G =
C).
These two discoveries, known as Chargaffs rules, indicated that DNA was more
variable than previously thought, and that it had a unique composition in each
species. These properties made DNA a much more plausible candidate for the
genetic material. Although Chargaffs findings were not completely understood
when he published his work in 1950, they would play a key role in the later
determination of DNAs structure.

The race to the double helix

By the early 1950s, although some scientists remained skeptical, it was becoming
increasingly clear that DNA was the hereditary material. A number of research
groups began to focus seriously on the structure of DNA in an effort to understand
how it could carry genetic information. Among those jockeying for the prize were
the young American biologist James Watson and the British physicist Francis
Crick, who set out to answer these questions by building three-dimensional
chemical models of DNA (first using cardboard cutouts and later switching to metal
ball-and-stick structures)2 .
Rather than carrying out experiments in the lab, Watson and Crick primarily
collected and analyzed existing pieces of experimental data, putting them
together in new and insightful ways. Some of their most crucial pieces of evidence
came from the work of Rosalind Franklin, a chemist then working in the lab of
physicist Maurice Wilkins at Kings College in England. Franklin was a leading
expert on a novel and powerful technique for determining the structure of
molecules, known as X-ray crystallography. X-ray crystallography requires a very
pure sample of a molecule in crystalline form and, as the name implies, a
concentrated source of X-rays. When a crystal is exposed to X-rays, some of the
rays will be deflected by the atoms in the crystal, forming a diffraction pattern that
gives clues about the arrangement of atoms in the molecule (as shown below).
Franklins crystallography gave Watson
and Crick important clues to the
structure of DNA. Some of these came
from the famous image 51, a
remarkably clear and striking X-ray
diffraction image of DNA produced by
Franklin and her graduate student. (A
modern example of the diffraction
pattern produced by DNA is shown at
right.) To Watson, the X-shaped
diffraction pattern of Franklin's image
immediately suggested a helical, twostranded structure for DNA3 . Watson
Image modified from "DNA structure and
and Crick gathered additional
sequencing: Figure 2," by OpenStax
information from an unpublished
College, Biology (CC BY 3.0).
report by Franklin, which provided
insight into the dimensions of the helix
and the relative orientations of the two strands, details that proved crucial to their
model3,4,5 . Franklin's report also included her conclusion that the hydrophilic

(water-loving) sugar-phosphate backbone of each DNA strand was on the outside

of the molecule, while the hydrophobic (water-fearing) nitrogenous bases were
packed in the interior6 .
[Did Watson and Crick steal Franklin's data?]

Watson and Crick used the information gathered by a number of researchers

(including Franklin, Wilkins, Chargaff, and others) to assemble their celebrated
model of the 3D structure of DNA, which was published in the scientific journal
Nature in 1953. Nine years later, they and Maurice Wilkins were awarded the
Nobel Prize in Physiology or Medicine for their discovery. Sadly, Franklin passed
away in 1958 and was thus ineligible to receive the prize. Although just three
researchers were recognized by the Nobel Committee, the discovery of DNA
structure was built on the efforts of many scientists across the globe, working in
various disciplines over the course of decades.

Watson and Crick's model of DNA

Watson and Cricks model was remarkably accurate and has only undergone
minor revisions in the sixty years since it was first proposed. The structure of DNA,
as represented in their model, is a double-stranded, antiparallel, right-handed
helix. The sugar-phosphate backbones of the DNA strands make up the outside of
the helix, while the nitrogenous bases are found on the inside and form hydrogenbonded pairs that hold the DNA strands together. We'll discuss each of these
features in greater detail below.
To visualize the overall structure of Watson and Crick's model, it's helpful to start
by imagining the structure of DNA as a ladder. The outside rails of the ladder are
like the sugar-phosphate backbones of the two DNA strands, and the interior
rungs of the ladder are like the pairs of nitrogenous bases. If you imagine the
ladder being flexible, so that you can twist it into a spiral, it begins to roughly
resemble the double helix of DNA.

Antiparallel orientation
Double-stranded DNA is an antiparallel molecule, composed of two strands that
run alongside each other but point in opposite directions. It's possible to say that
DNA strands "point" in certain directions because their two ends are structurally
different from one another. Specifically, the 5 end (pronounced five-prime) of a
DNA strand carries an exposed phosphate group, while the 3 end (pronounced
three-prime) carries an exposed hydroxyl group. In a double-stranded DNA
molecule, the 5' end of one strand aligns with the 3' end of its partner, and vice
versa. If we represent the directions of DNA strands with arrows pointing from 5' to
3', as shown in the diagram below, the arrows of the two strands of the double
helix point in opposite directions.

Image modified from "DNA chemical structure," by Madeleine Price Ball

(CC0/public domain).
To understand why DNA strands have 5' and 3' ends (and where the ends get
their names), it's helpful to consider how strands of DNA are assembled. Each
strand is made up of nucleotides, and the nucleotides are linked by
phosphodiester bonds that form between the hydroxyl group (3' hydroxyl) of one
nucleotide and the phosphate group (5 phosphate) of the next. These chemical
groups get their names from their positions: the 3' hydroxyl is attached to the 3rd
carbon atom of the sugar, while the 5 phosphate is attached to the 5th carbon
atom of the sugar, as defined by a conventional numbering scheme. Most of the
phosphate and hydroxyl groups in a DNA strand end up in phosphodiester
linkages, but the nucleotides at the ends of the chain lack neighbors and thus
have exposed groups: a phosphate group at one end (the 5' end) and a hydroxyl
group at the other (the 3' end).
[What is the purpose of the prime marks in 3' and 5'?]

Right-handed helix
In Watson and Crick's model, the two
strands of DNA twist around each
other to form a right-handed helix. All
helices have handedness, a property
that describes how their grooves are
oriented in space.
To understand what makes a helix
right-handed, imagine wrapping your
right hand around the DNA molecule
shown in the figure, with your thumb
pointing upwards. Now picture your
fingers sliding along the outside of the
spiral. Your hand should be moving
with the spirals, upwards, in the
direction your thumb is pointing.

Image modified from "DNA structure and

sequencing: Figure 3," by OpenStax
College, Biology (CC BY 3.0).

Because the right hand moves in the same direction as its thumb points as it slides
along the spirals, the DNA double helix can be identified as right-handed. If you
were to try the same thing with your left hand (thumb pointing up), your hand
would instead slide downward, opposite to the direction in which its thumb is
pointing.
[Are DNA helices always right-handed?]

The twisting of the DNA double helix, together with the geometry of the
nitrogenous bases, creates a wider gap (called the major groove) and a narrower
gap (called the minor groove) that run along the length of the molecule, as shown
in the figure at right. These grooves are important binding sites for proteins that
maintain DNA and regulate gene activity.

Base pairing
In Watson and Crick's model, the two strands of the DNA double helix are held
together by hydrogen bonds between nitrogenous bases on opposite strands. The
sugar-phosphate backbones of the DNA strands are found on the outside of the
helix, while the bases are positioned in the interior. Each pair of bases lies flat,
forming a "rung" on the ladder of the DNA molecule. Most importantly, the base
pairs aren't made up of just any combination of bases. Instead, if there is an A
found on one strand, it must be paired with a T on the other (and vice versa).
Similarly, an G found on one strand must always have a C for a partner on the
opposite strand. These A-T and G-C associations are known as complementary
base pairs, reflecting that the bases physically complement one other, sort of like
biochemical puzzle pieces (as we'll see below).
How did Watson and Crick figure out
the rules of base pairing? Thanks to
Franklins data, they knew that the
double helix had a uniform diameter of
roughly 2 nm. Although Watson
initially favored a model in which
similar bases paired (A with A, T with T,
etc.), such pairings could not explain
the uniform width of the helix9 . That's
because the bases are not all the
same size; instead, the one-ring
pyrimidines are smaller than the tworing purines. If purines were paired
with purines (and pyrimidines with
Image modified from "DNA structure and
pyrimidines), the diameter of the helix
sequencing: Figure 1," by OpenStax
would vary with each base pair.
College, Biology (CC BY 3.0).
However, if a purine were always
paired with a pyrimidine, the diameter
of the helix would remain constant, matching Franklins measurements.
Rather than allowing any purine to pair with any pyrimidine, Watson and Crick's
model further specified that A must pair only with T, and C only with G. Initially,
Watson arrived at these pairings through trial and error. After realizing that "like
with like" base pairing wouldn't work, he started experimenting with cardboard
cutouts of the bases, trying to see which ones might hydrogen bond with each

other (given their different chemical structures)9 . As he soon found, A and T had
just the right shapes to form hydrogen bonds with one another, as did G and C.
Although Watson and Crick's original model proposes that there are two hydrogen
bonds between the bases of each pair, we know today that G and C form an
additional bond (such that A-T pairs form two hydrogen bonds total, while G-C
pairs form three)10 .

Image modified from "DNA structure and sequencing: Figure 3," by OpenStax
College, Biology (CC BY 3.0).
Not only were A-T and G-C base pairs exactly the same width, accounting for the
uniform width of the helix, but they also provided an explanation for an older piece
of data. Chargaff had observed that, in every organism, the proportion of A
equaled that of T, while the proportion of G equaled that of C. If an A on one
strand always paired with a T on the other (and if a G always paired with a C),
Chargaff's data could be neatly explained11 .

DNA structure and replication

In their paper, Watson and Crick made what was probably a deliberate
understatement: It has not escaped our notice that the specific pairing we have
postulated immediately suggests a possible copying mechanism for the genetic
material" 10 . In fact, this was one of the most exciting aspects of their model: the
complementarity (strict matching of bases) between the two strands of the helix
meant that each could act as a template for synthesis of the other, allowing one
DNA molecule to be faithfully copied into two. As well see in later articles, the vital
cellular processes of DNA replication and gene expression both depend on the
principle of complementary base pairing.
[References]

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With the DNA structure how is it twisted shouldn't be

strait?
2 Votes

Comment Flag

about a month ago by

Adi.price

It's twisted to condense down for chromosomes

4 Votes

Comment Flag

29 days ago by

Servahn Hills

Show all 2 answers Answer this question

What is a codon and how does it relate to a DNA function
and structure ?
3 Votes

Comment Flag

2 months ago by

jakduir1

A codon is the name for a group of three subsequent

nucleotides in RNA. Since RNA is transcribed from
DNA, the DNA sequence will determine the sequence
of RNA, the codons, and ultimately what amino acids
come together to form a protein. If a DNA sequence
(template strand) goes CTTAGG, the corresponding
RNA will read GAAUCC. In this sequence there are
two codons: GAA followed by UCC, which will code
for amino acids.
2 Votes

1 Comment Flag

2 months ago by

Natassja Ellen Brien

Show all 2 answers Answer this question

well I have 2 doubts:
1) in the second para under the topic 'right hand helix' i
couldn't understand as to why DNA is a right handed
helix
2) in the second para under the topic 'base pairing' how
exactly is the bigger size of purines and small size of
pyramidines affecting the bond length?
2 Votes

Comment Flag

12 days ago by

Answer this question...

samarth6899

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