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Biochemistry > Chapter 7: Ligand Binding and Hemoglobin > Flashcards

Chapter 7: Ligand Binding and Hemoglobin Flashcards

1
Q

In a protein:ligand interaction, what does the ‘free’ state describe?

A

The state in which the protein (enzyme) and ligand (substrate) are still separated.

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2
Q

In a protein:ligand interaction, what does the ‘bound’ state describe?

A

When the protein (enzyme) and ligand (substrate) have bound together

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3
Q

What is a ligand?

A

A substrate

Any molecule that binds to a protein

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4
Q

What is an apoprotein?

A

A protein (enzyme) that has an empty binding site

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5
Q

What is a holoprotein also called?

A

Holoenzyme

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6
Q

What is a holoenzyme also called?

A

Holoprotein

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7
Q

What is a holoprotien/holoenzyme?

A

A protein (enzyme) that is bound to a ligand (has an occupied binding site)

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8
Q

What is a cofactor?

A

A non-chemical components that an enzyme needs in order to become catalytic

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9
Q

What are the 5 types of bonds that can occur between the proteins (enzymes) and ligands (substrates)?

A 
H bonds
Hydrophobic interactions
Electrostatic interactions
Dipole-Dipole interactions
(Rarely) covalent interactions
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10
Q

What are the two models for describing how proteins interact with ligands?

A
  1. Lock and key model

2. Induced fit model

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11
Q

Which interaction model is more suitable for living things: lock and key model or induced fit model?

A

Induced fit

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12
Q

Why is ‘induced fit’ model more compatible with life than ‘lock and key’ model?

A

Lock and key model is generally irreversible. Living things need interactions to be reversible.

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13
Q

Why is the lock and key model of protein:ligand interaction regarded as irreversible?

A

The fit between the protein and ligand is so perfect/energetically favorable that breaking the bind isn’t worth the extra energy cost.

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14
Q

What is an ES complex?

A

What you call it when the active site in the protein/enzyme is bound to the ligand/substrate

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15
Q

What does ‘ligand specificity’ describe?

A

THe fact that proteins can recognize specific ligands

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16
Q

What does hexokinase do?

A

It converts glucose to glucose phosphate

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17
Q

Why did Dr. Shimko tell us about hexokinase?

A

To show up how a protein/enzyme can change shape (conformation) and close around a ligand once the ligand binds to the protein’s active site.

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18
Q

Do binding events (like the one between hexokinase and its ligand) impact the corresponding protein folding funnel?

A

Yes

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19
Q

What are the 2 ways to describe/characterize an interaction between a protein and ligand?

A

stability (how strong the bond is)

Specificity (how specific/selective the protein is about which ligands it will bind to)

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20
Q

Why did Dr. Shimko tell us about alcohol dehydrogenase?

A

To show an example of how proteins with high specificity preferentially bind to some ligands rather than others

In this case, alcohol dehydrogenase can bind to ethanol, methanol, AND isopropanol, but prefers and works fastest with ethanol

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21
Q

Does a large Kd mean an ES complex is strong or weak?

A

A large Kd means the bond holding together the ES complex is weak

Kd = reactants over complex
Kd = free state over bound state
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22
Q

Does a small Kd mean an ES complex is strong or weak?

A

Strong

Kd = reactants over complex
Kd = free state over bound state
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23
Q

What does the Kd represent in terms of ligand concentration?

A

Kd tells you the concentration of ligand you need in order to convert half a sample of proteins from their free state to their bound state

If the Kd is low, it means you must’ve needed a lot of ligand in order to get half of your protein bound (because the affinity/tendency of partners to stick and stay stuck is poor)

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24
Q

(Conceptually), what are Ka and Kd measures of?

A

Affinity (binding strength); The tendency of a molecule to stick to its binding partner and stay stuck

The binding strength between a protein and its ligand

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25
Q

True or false: the higher the binding affinity between binding partners, the lower concentrations you will need to facilitate binding.

A

True.

Because the binds stay bound when they collide rather than falling apart and having to find each other/collide again in order to get a good bind.

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26
Q

True or false: the higher the affinity, the LOWER the Kd.

A

True

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27
Q

You may as well think of Kd as K divorce. Why?

A

Because Kd is an expression of how many bound proteins end up free (‘divorced’) proteins

Having a low Kd is like having a low divorce rate; means the couples are strong.

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28
Q

What range of Kd values are so strong that the corresponding bonds can scarcely be broken without denaturing the protein?

A

Kd = 10^-9 M and lower

Anything around the nanomolar range and lower

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29
Q

What range of Kd values is ideal for making drugs?

A

Kd around the “nanomolar to subnomolar range”

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30
Q

what is metabolic catalysis?

A

the break down of fuel sources

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31
Q

why is oxygen transport important?

A

All the cells in the body need molecular oxygen, but not all of them are exposed to molecular oxygen. The oxygen must thus be spread around the body.

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32
Q

why do we need oxygen in metabolic catalysis?

A

We need it to maximize production of ATP (energy)

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33
Q

What is the major role of hemoglobin in the body?

A

It is the primary transporter for oxygen

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34
Q

What is the main (structural) difference between myoglobin and hemoglobin?

A

Myoglobin is a monomer and hemoglobin is a tetramer

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35
Q

Is myoglobin an alpha helix or a beta sheet?

A

(Primarily) Alpha Helix

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36
Q

What 2 main components make up a myoglobin molecule?

A

A heme ring surrounded by alpha helices

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37
Q

What is a heme ring?

A

A Large aromatic system that has iron in the center and act as a cofactor

38
Q

Why is heme important in oxygen transport?

A

The iron in the center of the heme is what binds to the oxygens

39
Q

How many bonds can the iron at the middle of a heme make (total)?

A

6

40
Q

How are iron’s 6 bonds distributed (when it’s at the center of the myoglobin heme)?

A

4 of them are bound to nitrogens in the heme ring
1 is bound to a histidine in the myoglobin
1 is available to bind to oxygen

41
Q

When can iron make 6 bonds?

A

When it’s in the 2+ state

42
Q

Where in the body is myoglobin abundant?

A

Muscle tissue

43
Q

Is oxygen a ligand?

A

Yes; It’s the ligand to myoglobin and hemoglobin

44
Q

What are the units for plotting the O2 ligand on a dissociation graph?

A

Partial pressure (atm ,torr, kPa etc)

45
Q

What is a P_50?

A

What you call the halfway point on a dissociation graph where the ligand is a gas (like oxygen)

The point where 50% of the proteins are in the bound state (with a gas ligand) is called the P_50

The P is for pressure?

46
Q

Why isn’t myglobin as good as hemoglobin?

A

Its affinity to O2 is so high that it sticks to oxygen but scarcely gets unstuck in order to allow the oxygen to be given to other cells.

Myoglobin is good for oxygen storage but not oxygen transport

47
Q

If myoglobin is so bad at transporting oxygen, why do we have it?

A

It’s good at storing oxygen. Under the right conditions (like when your exerting yourself), the myoglobin will eventually give up the oxygen.

48
Q

Which animals especially benefit from myoglobin?

A

Deep diving mammals

49
Q

What 2 identical proteins is hemoglobin made of?

A

2 alpha proteins and 2 beta proteins

50
Q

How many O2 molecules can each hemoglobin subunit bind to?

A

1 per subunit (for a total of 4 O2 molecules across the entire hemoglobin molecule)

51
Q

What is the difference between hemoglobin T state and hemoglobin R state?

A

T state’s Fe2+, having no O2 bound to it, has that too big, puckered shape that throws off all the other nearby structures and subunits

R state’s Fe2+, having O2 bound, has the correct, less sterically hindered shape

52
Q

What happens to the (hemoglobin) heme’s Fe2+ shape when it isn’t bound to an oxygen?

A

It swells such that it doesn’t fit as snuggly inside the middle of the heme ring. This causes a slight bend in the ring that disrupts the planar conformation heme ring, which strains the aromaticity.

This, in turn, throws off the conformation of the neighboring histidine

53
Q

How does binding to an oxygen help the (hemoglobin’s) Fe2+ maintain the size needed for fitting snuggly in the heme ring?

A

When the oxygen binds, it pulls e- density away from the center of the Fe2+, allowing it to shrink down to the appropriate size.

This also corrects the orientation of the neighboring histidine and all the other subunits in the hemoglobin.

54
Q

What does the ‘T’ in ‘T state hemoglobin’ stand for?

A

Tense (because it’s more sterically hindered)

55
Q

What does the ‘R’ in ‘R state hemoglobin’ stand for?

A

Relaxed state

56
Q

Which hemoglobin state has a ‘donut hole’ in the middle that can act as a binding site for regulatory molecules?

A

T state

57
Q

Is the transition between the two types of hemoglobin (T and R) reversible?

A

Yes

58
Q

What is allostery?

A

A mechanism for regulating enzyme activity

59
Q

What does it mean to say that a protein is allosteric?

A

It means the protein’s activity is regulated via allostery

60
Q

How does POSITIVE allostery work when you have a protein with multiple binding sites?

A

After the first binding site becomes occupied, the binding site changes shape, and that shape change propagates across the entire protein such that other binding sites become more likely to become occupied, as well.

See photos

61
Q

How does NEGATIVE allostery work when you have a protein with multiple binding sites?

A

Binding of a ligand decreases the protein’s activity; Binding at one site DISCOURAGES binding at additional sites.

After the first binding site becomes occupied, the binding site changes shape, and that shape change propagates across the entire protein such that other binding sites become LESS likely to become occupied, as well.

See photos

62
Q

What does homotropic allostery describe?

A

When a protein that is being regulated via allostery has multiple binding sites for the SAME ligand

63
Q

What does HETEROallostery describe?

A

When a protein being regulated via allostery has multiple binding sites but they’re for DIFFERENT ligands

64
Q

What is the key take away about the allostery mechanism?

A

That binding at one site on a protein influences binding at other sites on the protein.

That Binding at one site changes the likelihood that there will be binding at another site

65
Q

Does negative allostery increase or decrease Kd for the second binding site?

A

Increase

66
Q

Does positive allostery increase or decrease Kd for the second binding site?

A

Decrease

67
Q

What is the shorthand for a T hemoglobin?

A

4 circles

68
Q

What is the short hand for an R hemoglobin?

A

4 squares

69
Q

Is molecular oxygen a positive allosteric regulator for hemoglobin or a negative allosteric regulator?

A

Positive; each bound molecular oxygen encourages binding of more molecular oxygens

70
Q

What are the 2 models used to describe how molecular oxygen binds to hemoglobin cooperatively?

A

Concerted model

Sequential model

71
Q

Why do we have 2 models for describing how hemoglobin binds cooperatively to molecular oxygen?

A

Neither of the models alone completely/correctly describes every aspect of the way that hemoglobin binds cooperatively to molecular oxygen.

Where one model fails, the other succeeds (and vice versa)

72
Q

What is the main point of the concerted model (of describing oxygen binding to hemoglobin)?

A

That hemoglobin exists at either T or R and that binding oxygens simply shifts the equilibrium between the two states

73
Q

What is the limitation of the concerted model (of describing how oxygen binds to hemoglobin cooperatively)?

A

It doesn’t account for how T state hemoglobins change shape bit by bit (to adopt a more R like shape) with each new oxygen that is added.

It describes an equilibrium between two fixed states (T and R) rather than describing T-ness and R-ness being part of a spectrum

74
Q

Which came first: concerted model or sequential model?

A

Concerted

75
Q

What is the main point of the sequential model (of describing oxygen binding to hemoglobin)?

A

As you add oxygens to T state, the affinity increases (equilibrium shifts towards R-like affinity) AND the R like character of the hemoglobin’s shape increases

See pictures!

76
Q

What is the limitation of the sequential model (for describing how oxygens bind to hemoglobins)?

A

It proposes that the only the time the R states exists is when all 4 of a hemoglobins hemes are occupied with oxygen…

(this is a problem because in nature and in experiments we see that R state actually predominates when a hemoglobin has as few as 3 hemes occupied with oxygen, as correctly captured by the concerted model)

77
Q

What triggers an R state hemoglobin to lower its affinity (release its oxygens/‘sample’ the T state)

A

A relatively low local concentration of oxygen (such as what could be found in the muscles)

78
Q

Is carbon monoxide an allosteric regulator (for hemoglobin)?

A

Yes (if dangerously so)

79
Q

How does carbon monoxide work as a poison?

A

When it binds to hemoglobin, it blocks oxygen from being able to bind AND it traps the hemoglobin in a R state (meaning that even if it had any oxygens on its binding sites along side the CO, it couldn’t release them)

80
Q

What does it mean to say that someone has 50% hemoglobin saturation?

A

That only half of their hemoglobin hemes are carrying oxygen

81
Q

What are the treatments for CO poisoning?

A
  1. Get a blood transfusion (receive blood that doesn’t have CO stuck to it)
  2. Wait for the affected hemoglobin to die and be cleared by the body naturally (hemoglobin half life is about 120 days)
82
Q

How does pH impact Hb affinity?

A

As pH goes down, Hb affinity goes down

The extra H+ in the system binds to Hb and stabilizes the T state

83
Q

Why does decreased pH decrease Hb affinity?

A

Because decreased pH means the body needs Hb to release its O2. Affinity myst lower/Hb must take on more T character in order to accommodate this.

84
Q

True or false: negative allosteric Hb regulators work by preferentially stabilizing the T state conformation.

A

true

85
Q

which allosteric regulator binds to the T state donut hole in order to stabalize the T state?

A

2,3,-BPG

86
Q

which allosteric regulator binds to the R state heme blocks it’s ability to bind new O2 AND blocks it ability to release old O2?

A

CO

87
Q

How many allosteric regulators are there for Hb?

A

4

88
Q

Which allosteric regulator protonates R state His at low pH, enabling the Hb to engage in T state stabilizing salt bridges?

A

H+

89
Q

Which allosteric regulator has direct and indirect action: H+ or CO2?

A

CO2

90
Q

How does CO2 DIRECTLY stabilize T state Hb?

A

It binds to the N terminus, creating a carbamate that can participate in T state stabilizing salt bridge

91
Q

How does CO2 INdirectly stabilize T state Hb?

A

It causes an increase in H+ via Le Chatlier’s principle

92
Q

How do salt bridges stabilize the T state?

A

???

It adds bulk

Biochemistry (23 decks)

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