Chapter 4 The Transform More Stable And The

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Chapter 4

The Three-Dimensional Structure of Proteins

SUMMARY

Section 4.1

 Proteins are made up of long chains of amino acids. The composition and order

of the amino acids are critical to the protein function.

 For any native protein, there is one, or at most a few, three dimensional

Section 4.2

 The primary structure of a protein determines the other levels of structure

 A single amino acid substitution can give rise to a malfunctioning protein, as in

the case with sickle-cell anemia.

Section 4.3

 Secondary structures are based upon periodic structures of the peptide

backbone.

 The most common secondary structures are the -Helix and -Sheet.

Section 4.4

 Tertiary structure is the complete three-dimensional arrangement of all the atoms

in a protein.

 The tertiary structure of proteins is maintained by different types of covalent and

non-covalent interactions.

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 Proteins can be denatured by heat, pH, and chemicals. Denaturation causes the

protein to lose its native tertiary structure.

 Some types of denaturation can be reversed, while others are permanent.

Section 4.5

 Quaternary structure is the final level of protein structure and pertains to those

proteins that consist of multiple polypeptide chains. Each chain is called a

subunit.

 Hemoglobin’s affinity for oxygen is controlled by several factors including oxygen

pressure and pH. When the pH drops or when oxygen pressure is low,

hemoglobin tends to release more oxygen to the tissues. When the pH is high

and oxygen is plentiful, such as at the lung-blood interface, hemoglobin binds

oxygen.

Section 4.6

 Using the power of computers, we can now predict the tertiary structure of a

protein if we know its amino acid sequence.

 A great deal of information regarding protein structure and sequences can be

found on the World Wide Web.

The Three-Dimensional Structure of Proteins 3

LECTURE NOTES

This chapter presents details on the general structure of proteins. The

hierarchical nature of the four levels of structure in proteins leading to the final three-

LECTURE OUTLINE

I. Protein structure linked to function

A. Native versus denatured conformations

B. Levels of protein structure and the forces holding them together

1. Primary – peptide bonds

II. Primary structure

III. Secondary structure

A. Peptide planes, Φ and  angles

B. The α-helix

1. Position of hydrogen bonds

C. The β-sheet

D. Other structures

1. Bulges and turns

IV. Tertiary structure

A. Use of X-ray crystallography and NMR studies

B. Myoglobin as an example of protein structure

1. Folding around heme

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VI. Quaternary structure

A. Hemoglobin as an example of protein structure

B. Conformational changes and hemoglobin function

3. Effects of BPG binding

VII. Thermodynamics and protein folding

A. Weak forces

ANSWERS TO PROBLEMS

4.1 Protein Structure and Function

1. (a) (iii); (b) (i); (c) (iv); (d) (ii).

2. When a protein is denatured, the interactions that determine secondary, tertiary,

3. The random portions of a protein do not contain structural motifs that are

4.2 Primary Structure of Proteins

4. When a protein is covalently modified, its primary structure is changed. The

(a) Serine has a small side chain that can fit in any relatively polar environment.

(b) Tryptophan has the largest side chain of any of the common amino acids, and it

tends to require a nonpolar environment.

would not affect the side-chain pKa in a significant way. Similar reasoning applies

to the substitution of a nonpolar isoleucine for a nonpolar leucine.

meat.

4.3 Secondary Structure of Proteins

9. Shape, solubility, and type of biological function (static, structural versus

dynamic, catalytic).

The Three-Dimensional Structure of Proteins 5

10. The angles of the amide planes as they rotate about the -carbon. The angles

are both defined as zero when the two planes would be overlapping such that the

13. The -helix is not fully extended, and its hydrogen bonds are parallel to the

protein fiber. The -pleated sheet structure is almost fully extended, and its

hydrogen bonds are perpendicular to the protein fiber.

14. The  unit, the  unit, the -meander, the Greek key, and the -barrel.

18. Wool, which consists largely of the protein keratin, shrinks because of its –

helical conformation. It can stretch and then shrink. Silk consists largely of the

protein fibroin, which has the fully extended -sheet conformation, with far less

tendency to stretch or shrink.

4.4 Tertiary Structure of Proteins

19. See Figure 4.2 for a hydrogen bond that is part of the -helix (secondary

structure). See Figure 4.12 for a hydrogen bond that is part of tertiary structure

23. Configuration refers to the position of groups due to covalent bonding. Examples

include cis and trans isomers and optical isomers. Conformation refers to the

positioning of groups in space due to rotation around single bonds. An example

is the difference between the eclipsed and staggered conformations of ethane.

24. Five possible features limit possible protein configurations and conformations. (1)

Although any one of 20 amino acids is possible at each position, only one is

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25. Technically, collagen has quaternary structure because it has multiple

4.5 Quaternary Structure of Proteins

26. Similarities: both contain a heme group; both are oxygen binding; secondary

structure is primarily -helix. Differences: hemoglobin is a tetramer, while

29. The function of hemoglobin is oxygen transport; its sigmoidal binding curve

reflects the fact that it can bind easily to oxygen at comparatively high pressures

and release oxygen at lower pressures. The function of myoglobin is oxygen

storage; as a result, it is easily saturated with oxygen at low pressures, as shown

by its hyperbolic binding curve.

30. In the presence of H+ and CO2, both of which bind to hemoglobin, the oxygen–

binding capacity of hemoglobin decreases.

31. In the absence of 2,3–bisphosphoglycerate, the binding of oxygen by hemoglobin

34. Deoxygenated hemoglobin is a weaker acid (has a higher pKa) than oxygenated

hemoglobin. In other words, deoxygenated hemoglobin binds more strongly to H+

35. The primary flaw in your friend’s reasoning is a reversal of the definition of pH,

which is pH = –log [H+]. If the release or binding of hydrogen ion by hemoglobin

36. The change of a histidine to a serine in the -chain removes a positively charged

37. People with sickle-cell trait have some abnormal hemoglobin. At high altitudes,

there is less oxygen, and the concentration of the deoxy form of the abnormal

The Three-Dimensional Structure of Proteins 7

hemoglobin increases. Less oxygen can be bound, causing the observed

breathing difficulties.

38. In fetal hemoglobin, the subunit composition is 22 with replacement of the –

4.6 Protein Folding Dynamics

42. On the β chain of HbS there is a valine at position 6 where there is a glutamic

acid on the normal form.

43. Valine is a hydrophobic amino acid. The valine is on the outside of the globular

prone to malaria.

45. Hydroxyurea stimulates the bone marrow to produce fetal hemoglobin. Fetal

hemoglobin has no β chain, so the effects of the interactions of those chains is

reduced in the presence of increased HbF.

46. BCL11A is a protein that represses the production of HbF. It is relevant because

47. The theory is the HbF evolved so that the fetal hemoglobin would have a higher

affinity for oxygen than the mother’s adult hemoglobin. This would favor transfer

of oxygen from the mother to the fetus. Is there a downside to this in the adult?

48. This level of sequence homology is marginal for use of comparative modeling. It

is best to try that method, but then to compare the results with those obtained

from the fold-recognition approach.

49. Protein folding is driven by many processes. The intuitive ones are the direct

interactions of functional groups through covalent bonds, electrostatic attractions,

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why nonpolar regions of the protein tend to cluster together, usually in the interior

50. See the Protein Data Bank.

51. A chaperone is a protein that aids another protein in folding correctly and keeps it

from associating with other proteins before it has reached its final, mature form.

52. A prion is a potentially infectious protein found in multiple forms in mammals,

53. A series of encephalopathies have been found to be caused by prions. In cows,

54. The normal form of the prion protein has a higher -helix content compared to

the -sheet content. The abnormal one has an increased -sheet content.

55. Alzheimer’s, Parkinson’s, and Huntington’s diseases are caused by accumulation

of protein deposits from aggregates caused by misfolded proteins. This chapter

56. Protein aggregates form when there are exposed areas on a protein surface that

57. The root problem with the globin genes and potential issues with hemoglobin

formation is based on the fact that there are two α–globin genes for every β–

58. The sequence of the mutant prion that confers the most extreme sensitivity to

conferring a prion disease is the substitution of the amino acid at position 129 to

a methionine.

59. Prion diseases are transmissible, while other neurodegenerative diseases like

The Three-Dimensional Structure of Proteins 9

61. The two enzymes associated with the disease are called β– secretase and γ–

secretase.

62. Amyloid β and Tau are the two proteins that form destructive plaques. The

63. Alzheimer’s begins with the buildup of Aβ, which is cut from the APP. In the first

step, the enzyme β–secretase cuts APP outside the cell membrane. Then the γ–

secretase enzyme cuts the remaining portion of the APP inside the membrane,

releasing Aβ.

64. β-secretase is naturally involved with the myelination of nerves.

65. Prion diseases have been linked to the immune system. It is believed that the