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Biochemistry of Medicinals I – Nucleic Acids

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

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slide1
Biochemistry of Medicinals I – Nucleic Acids

Instructor: Natalia Tretyakova, Ph.D.

760E CCRB (Cancer Center)

Tel. 6-3432

e-mail [email protected]

Lecture: MWF 2:30-3:20 7-135 WDH

Web page: see “Web enhanced courses”

chapter 1 dna structure
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)

dna structure chapter outline
DNA Structure: Chapter outline
  • Biological roles of DNA. Flow of genetic information.
  • Primary and secondary structure of DNA.
  • Types of DNA double helix. Sequence-specific DNA recognition by proteins.
  • Biophysical properties of DNA.
  • DNA topology. Topoisomerases.
  • Restriction Endonucleases. Molecular Cloning
slide5
(ribonucleic acids)

(deoxyribonucleic acids)

replication

transcription

translation

DNA

slide6
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
the building blocks of dna
The Building Blocks of DNA

-N-glycosidic bond

dna and rna nucleobases
DNA and RNA nucleobases

(DNA only)

(RNA only)

slide11
nucleobase

(Deoxy)

nucleoside

5’-mononucleotide

Adenine (A)

Guanine (G)

Thymine (T)

Cytosine (C)

Uracil (U)

2’-Deoxyadenosine (dA)

2’- Deoxyguanosine (dG)

2’- Deoxythymidine

(dT)

2’- Deoxycytidine

(dC)

Uridine (U)

Deoxyadenosine 5’-monophosphate

(5’-dAMP)

Deoxyguanosine 5’-monophosphate

(5’-dGMP)

Deoxythymidine 5’-monophosphate

(5’-dTMP)

Deoxycytidine 5’-monophosphate

(5’-dCMP)

Uridine 5’-monophosphate (5’-UMP)

Nomenclature of nucleobases, nucleosides, and mononucleotides

dna is arranged 5 to 3 connected by phosphates
DNA isArranged5’ to 3’Connected byPhosphates

Linking inDNA biopolymer: DNA primary structure

dna secondary structure double helix
DNA secondary structure – double helix
  • James Watson and Francis Crick, 1953- proposed a model for DNA structure
          • 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

Francis Crick Jim Watson

slide17
Watson-Crick model of DNA was based on X-ray

diffraction picture of DNA fibres

(Rosalind Franklin and Maurice Wilkins)

Rosalind Franklin

slide18
Watson-Crick model of DNA was consistent with Chargaff’s base composition rules

Erwin Chargaff (Columbia University)

G = C and A = T in DNA

slide22
Forces stabilizing DNA double helix
  • Hydrogen bonding (2-3 kcal/mol per base pair)
  • Stacking (hydrophobic) interactions
  • (4-15 kcal/mol per base pair)
  • 3. Electrostatic forces.
slide23
B-DNA
  • •Sugars are in the 2’ endo conformation.
  • •Bases are the anti conformation.
  • •Bases have a helical twist of 36º
  • (10.4 bases per helix turn)
  • Helical pitch = 34 A

23.7 A

right handed helix

  • helical axis passes through
  • base pairs

7.0 A

  • planes of bases are nearly
  • perpendicular to the helix axis.
  • 3.4 A rise between base pairs

Wide and deep

Narrow and deep

slide24
DNA can deviate from the ideal Watson-Crick structure
  • Helical twist ranges from 28 to 42°
  • Propeller twisting 10 to 20°
  • Base pair roll
major groove and minor groove of dna
Major groove and Minor groove of DNA

N

NH

O

2

N

H

N

O

2

N

NH

N

N

N

HN

C-1’

N

N

N

N

C-1’

NH

O

O

2

C-1’

Hypothetical situation: the two grooves would have similar size if dR residues

were attached at 180° to each other

To deoxyribose-C1’

C1’ -To deoxyribose

C-1’

slide26
N

NH

2

H

N

O

2

N

N

HN

C-1’

N

N

NH

O

2

C-1’

Major and minor groove of the double helix

O

N

NH

N

N

N

N

C-1’

O

C-1’

Wide and deep

Narrow and deep

slide28
A-form helix:dehydrated DNA; RNA-DNA hybrids
  • •Sugars are in the 3’ endo conformation.
  • •Bases are the anti conformation.
  • •11 bases per helix turn
  • Helical pitch = 25.3 A

Right handed helix

  • planes of bases are tilted
  • 20 ° relative the helix axis.
  • 2.3 A rise between base pairs

25.5 A

Top View

slide31
Z-form double helix:polynucleotides of alternating purines and pyrimidines (GCGCGCGC) at high salt
  • • Backbone zig-zags because sugar puckers alternate between 2’ endo pyrimidines and 3’ endo (purines)
  • • Bases alternate between anti (pyrimidines) and syn conformation (purines).
  • •12 bases per helix turn
  • Helical pitch = 45.6 A

Left handed helix

  • planes of the bases are
  • tilted 9° relative the helix
  • axis.
  • 3.8 A rise between base pairs

18.4 A

• Flat major groove

• Narrow and deep minor groove

sugar and base conformations in z dna alternate
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

slide34
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
  • Structural variations play a role in DNA-protein interactions
  • RNA-DNA hybrids and ds RNA have an A-type structure
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