This document provides an overview of DNA structure and the different forms it can take. It discusses the primary structures of DNA including nucleotides, nucleosides, and bases. It then describes the canonical B-DNA double helical structure proposed by Watson and Crick, including base pairing, base stacking, and the forces that stabilize the structure. Finally, it briefly discusses alternative A-form and Z-form double helical structures and their biological relevance.

1. Biochemistry of Medicinals I – Nucleic
Acids
Instructor: Natalia Tretyakova, Ph.D.
760E CCRB (Cancer Center)
Tel. 6-3432
e-mail trety001@umn.edu
Lecture: MWF 2:30-3:20 7-135 WDH
Web page: see “Web enhanced courses”

3. Chapter 1. DNA Structure.
Required reading: Stryer 5th Edition p. 117-125, 144-146, 152, 745-750,
754-762, 875-877)
(or Stryer’s Biochemistry 4th edition p. 75-77,80-88, 119-122, 126-128,
787-799, 975-980)

4. DNA Structure: Chapter outline
1. Biological roles of DNA. Flow of genetic
information.
3. Primary and secondary structure of DNA.
5. Types of DNA double helix. Sequence-
specific DNA recognition by proteins.
7. Biophysical properties of DNA.
9. DNA topology. Topoisomerases.
11.Restriction Endonucleases. Molecular Cloning

5. Nucleic Acids
DNA RNA
(deoxyribonucleic acids) (ribonucleic acids)
Central Dogma of Biology
DNA RNA Proteins Cellular Action
replication
transcription translation
DNA

6. Why ?
Questions?
•How is genetic information transmitted to progeny cells?
•How is DNA synthesis initiated?
•What causes DNA defects and what are their biological an
physiological consequences?
•What causes the differences between cells containing the same
genetic information?
Relevance:
•Cancer: ex. Xeroderma pigmentosum
•Genetic diseases: ex., cystic fibrosis, sickle cell anemia, inborn
errors of metabolism
•Genetic typing: ex., drug metabolism
•Rational drug design: ex., antitumor and antimicrobial drugs
•Biotechnology: ex., growth hormones

7. The Building Blocks of DNA
Nucleotide
Purine or
Pyrimidine
O Base
5'
-O P O
O
β-N-glycosidic bond
1'
O- H H
4'
H 3' 2' H
O H(OH)
Phosphate
Pentose sugar
Nucleoside

8. DNA and RNA
nucleobases
NH2 O
7 6
N 5 1 N N
N N NH
8
4 2 N N
9N N N H
N NH2
H H
3
Purine Adenine (A) Guanine (G)
NH2 O
O
4
3 H3C
5 N N NH
NH
6 2
N1 N O N O
H N O
H H H
Pyrimidine Cytosine (C) Thymine (T) Uracil (U)
(DNA only) (RNA only)

9. Purine Nucleotides

10. Pyrimidine Nucleotides

11. Nomenclature of nucleobases, nucleosides,
and mononucleotides
nucleobase (Deoxy) 5’-mononucleotide
nucleoside
Adenine (A) 2’-Deoxyadenosine Deoxyadenosine 5’-monophosphate
(dA) (5’-dAMP)
Guanine (G) 2’- Deoxyguanosine Deoxyguanosine 5’-monophosphate
(dG) (5’-dGMP)
Thymine (T) 2’- Deoxythymidine Deoxythymidine 5’-monophosphate
(dT) (5’-dTMP)
Cytosine (C) 2’- Deoxycytidine Deoxycytidine 5’-monophosphate
(dC) (5’-dCMP)
Uracil (U) Uridine (U) Uridine 5’-monophosphate (5’-UMP)

12. Structural differences between DNA and RNA
DNA RNA
O O
H3C
NH NH
N O N O
H H
Thymine (T) Uracil (U)
HO CH2 HO CH2
O Base O Base
H H H H
H H
H H
O H O OH
2'-deoxyribose ribose

13. Preferred conformations of nucleobases and sugars in
DNA and RNA
NH2 NH2
N N
HO N O O N
HO
O
O
OH
OH
Anti conformation Syn conformation
Sugar puckers:
5.9 A
HO HO HO
BASE 3' BASE
5' 2' 5'
O 1' O 1'
7.0 A 3' H (OH)
HO H (OH)
2' endo (B-DNA) 3' endo (RNA)

14. Nucleosides Must Be Converted to
5’-Triphosphates to be Part of DNA and
RNA
O
HO
HO P O Base
Base
O Kinase HO O
ATP
OH OH
Monophosphate
ATP Kinase
O O O O O
HO P O P O P O HO P O P O
Base Kinase Base
HO OH OH O HO OH O
ATP
OH OH
Triphosphate Diphosphate

15. Linking in DNA biopolymer: DNA primary structure
DNA is
Arranged
5’ to 3’
Connected by
Phosphates

16. DNA secondary structure – double
helix
James Watson and Francis Crick, 1953- proposed a model for DNA
structure
Francis Crick Jim Watson
•DNA is the molecule of heredity (O.Avery, 1944)
•X-ray diffraction (R.Franklin and M. Wilkins)
•E. Chargaff (1940s) G = C and A = T in DNA

17. Watson-Crick model of DNA was based on X-ray
diffraction picture of DNA fibres
(Rosalind Franklin and Maurice Wilkins)
Rosalind Franklin

18. Watson-Crick model of DNA was consistent with
Chargaff’s base composition rules
Erwin Chargaff (Columbia University)
G = C and A = T in DNA

19. DNA is Composed of
Complementary Strands
Anti-parallel Strands
DNA RNA of DNA
N
O
N
O 5' 3'
H 2N H 2N
N NH N NH
N N
N N N N A :: T
NH 2 O NH 2 O
G•C G•C
N N G :::C
NH 2 NH 2
N O O
N
N N
HN HN T :: A
N N
N N
O O
A•T A•U 3' 5'

20. Base Pairing is Determined by Hydrogen
Bonding
same size

21. Base stacking: an axial view of
B-DNA

22. Forces stabilizing DNA double
helix
1. Hydrogen bonding (2-3 kcal/mol per base pair)
3. Stacking (hydrophobic) interactions
(4-15 kcal/mol per base pair)
3. Electrostatic forces.

23. B-
DNA
23.7 A •Sugars are in the 2’ endo
right handed helix
conformation.
HO
• helical axis passes through 5' 2' BASE
base pairs O 1'
3' H (OH)
7.0 A
HO
• planes of bases are nearly
perpendicular to the helix axis.
•Bases are the anti conformation.
NH2
• 3.4 A rise between base pairs
N
Wide and deep HO N O
O
OH
•Bases have a helical twist of 36º
Narrow and deep (10.4 bases per helix turn)
• Helical pitch = 34 A

24. DNA can deviate from the ideal Watson-Crick structure
• Helical twist ranges from 28 to 42°
• Propeller twisting 10 to 20°
•Base pair roll

25. Major groove and Minor groove of DNA
Hypothetical situation: the two grooves would have similar size if dR residues
were attached at 180° to each other
To deoxyribose-C1’ Base Base C1’ -To deoxyribose
Major groove Major groove
N NH 2
O
N
H 2N O
N
N NH N
N HN
N C-1’ N
N N
C-1’ NH 2 O O
e C-1’ C-1’
os To
rib d eox
xy yri
deo bo
se Minor groove
To
Minor groove

26. Major and minor groove of the
double helix
Major groove
N O
H2N
N NH
N
N N
e C-1’ NH2 O
os C-1’T
y rib od
eox
ox yri
de bo
To Minor groove se
N NH 2
Wide and deep O
N
N
HN
C-1’ N
N
O
C-1’
Narrow and deep

27. B-type duplex is not possible for
RNA
HO CH2
O Base
H H
H
H
O OH
ribose
steric “clash”

28. A-form helix: dehydrated DNA; RNA-DNA hybrids
Right handed helix
•Sugars are in the 3’ endo
conformation.
• planes of bases are tilted
20 ° relative the helix axis.
•Bases are the anti conformation.
• 2.3 A rise between base pairs
25.5 A
•11 bases per helix turn
• Helical pitch = 25.3 A
Top View

29. The sugar puckering in A-DNA is 3’-endo
5.9 A
O
5' 2' BASE
O O
O 3' BASE
1' 5'
7.0 A 3' H (OH) 1'
O
O 2'
H (OH)
2' endo (3' exo) B-DNA 3' endo (A-DNA)

30. A-DNA has a shallow minor
groove and a deep major
groove
Major groove
N O H2N
Major groove
os
eN NH• N
N To d
Helix axis •
O H2N
ib N eo N
yr xy
e ox NH2 O rib
os
d e e N NH N
To Minor groove os N To d
ib N eo
yr xy
ox NH2 O rib
de os
e
To Minor groove
B-DNA A-DNA

31. Z-form double helix: polynucleotides of
alternating purines and pyrimidines (GCGCGCGC) at
high salt
Left handed helix
• Backbone zig-zags because sugar
puckers alternate between 2’ endo
pyrimidines and 3’ endo (purines)
• planes of the bases are
tilted 9° relative the helix
axis. • Bases alternate between anti
(pyrimidines) and syn conformation
(purines).
• 3.8 A rise between base pairs
•12 bases per helix turn
18.4 A • Helical pitch = 45.6 A
• Flat major groove
• Narrow and deep minor groove

32. Sugar and base conformations in Z-DNA
alternate:
5’-GCGCGCGCGCGCG
3’-CGCGCGCGCGCGC
C: sugar is 2’-endo, base is anti
G: sugar is 3’-endo, base is syn
NH2
O
N HN
H2N N
HO
N O
5' 2' N
HO HO
O 1' 3' N
5'
3' H
O 1'
HO
C G H

34. Biological relevance of the minor types of DNA
secondary structure
•Although the majority of chromosomal DNA is in B-form,
some regions assume A- or Z-like structure
• Runs of multiple Gs are A-like
•The upstream sequences of some genes contain
5-methylcytosine = Z-like duplex NH 2
H3C
N
N O
H
5-methylcytosine (5-Me-C)
• Structural variations play a role in DNA-protein interactions
• RNA-DNA hybrids and ds RNA have an A-type structure