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period 2 > Structural bioinformatics - protein structures > Flashcards

Structural bioinformatics - protein structures Flashcards

1
Q

What levels of protein structure are there?

A

Primary
Secondary
Tertiary
Quaternary

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2
Q

What is the primary structure of a protein?

A

The amino acid sequence

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3
Q

What is the secondary structure of a protein? What are the different secondary folds?

A

The first level of protein folding where in which the amino acid sequence form generic structures that exist in all proteins.

The secondary folds are
- alfa-helices
- beta sheets
- turns
-loops

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4
Q

What is the tertiary structure of a protein? What is the tertiary structure determined by?

A

Folding of the secondary structure elements. It is determined by the interactions between secondary structure elements.

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5
Q

What is the quaternary structure of a protein?

A

Consists of two or more proteins interacting with each other to form a biologically active unit. Not all proteins have a quaternary structure.

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6
Q

What does an amino acid consist of? What is the general structure of an amino acid

A

carbon
nitrogen
oxygen
hydrogen
sulfur (only in a small few)

The structure of an amino acid can be divided into the main chain and the side chain which gives the amino acid its chemical and physiological properties.

The amino acids have on one end an amino group and o the other a carboxyl group.

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7
Q

How is the primary structure of a protein formed?

A

A polypeptide chain is formed by peptide bonds.

The amino group and carboxyl group of two different amino acids interact and bond. Water is eliminated.

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8
Q

Why are all amino acids chiral molecules?

A

Because they have a side chain which means that all amino acids can be mirrored into different isomers.

Humans only have L-isomers.

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9
Q

How are the 20 amino acids divided into groups?

A

The side chains gives the amino acids different properties by which we can categorize them:

Non-polar

Charged polar (acidic and basic)

Uncharged polar

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10
Q

Which group of amino acids are hydrophobic vs hydrophilic?

A

The non-polar are hydrophobic

The polar are hydrophilic

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11
Q

What interactions does the non-polar vs the polar amino acids form?

A

The non-polar hydrophobic amino acids form Van her Waals interactions with each others side chains.

The polar hydrophilic amino acids typically form hydrogen bonds.

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12
Q

What makes a side chain acidic or basic?

A

acidic - COOH-group
basic - NH2 group

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13
Q

Name the non-polar (hydrophobic) side chains as well as their shortened names.

A

Alanine (Ala, A)
Valine (Val, V)
Leucine (Leu, L)
Isoleucine (Ile, I)
Proline (Pro, P)
Phenylalanine (Phe, F)
Methionine (Met, M)
Tryptophan (Trp, W)
Glycine (Gly, G)

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14
Q

Name the polar amino acids with a basic charge as well as their short names.

A

Lysine (Lys, K)
Arginine (Arg, R)
Histidine (His, H)

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15
Q

Name the polar acidic amino acids as well as their short names.

A

Aspartic acid (Asp, D)
Glutamin acid (Glu, E)

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16
Q

What does it mean that the charged amino acids are pH dependent?

A

It means that at a specific pH they can form acid-base reactions and at a physiological pH 7 the amino acids will have a positive or negative charge depending on what pH they react at.

At a pH below the pKa for each functional group on the amino acid, the functional group is protonated. At a pH above the pKa (acid dissociation constant) for the functional group, it is deprotonated - meaning that the functional group loses a proton. If the pH equals the pKa, the functional group is 50% protonated and 50% deprotonated. pKa can be altered by the local environment in proteins.

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17
Q

Name the neutral polar amino acids as well as they short names.

A

Asparagine (Asn, N)
Glutamine (Gln, Q)
Serine (Ser, S)
Threonine (Thr, T)
Tyrosine (Tyr, Y)
Cysteine (Cys, C)

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18
Q

What different interactions stabilize the polypeptide chains?

A

The strong covalent bonds:
- Covalent bond
- Disulfid bridge

The weaker non-covalent bonds:
- Salt bridges
- Hydrogen bonds
- Long range electrostatic interactions
- Van der Waals interactions

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19
Q

What is the pKa value?

A

It is the proton dissociation constant. It tells us if a functional group will give away or accept protons at certain pH values.

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20
Q

What kind of bond is the peptide bond? How is it formed?

A

A covalent bond.

It is formed in a condensation reaction - meaning that the reaction gives a loss of water.

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21
Q

What is an amino acid residue?

A

When two amino acids are linked together in a peptide bond, the individuals are called amino acid residues.

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22
Q

Why is the peptide bond important to the protein structure?

A

All of the atoms in the bond all lie in the same plane which limits rotation around the bond.

Both the -NH and -C=O groups are capable of non-covalent hydrogen bonding interactions which in the secondary structures are key to the folding of the protein chain.

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23
Q

What is the protein backbone/main chain? What are the N and and C terminals?

A

The peptide bonds and the connecting carbon molecules.

N-terminals = amino terminus (the left end)
C-terminals = carboxy terminus

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24
Q

What are dihedral/torsion angles? What is Phi and Psi?

A

The atoms at either end of a bond are free to rotate and torsion angles are used to define the conformation around bonds.

These angles describe the rotations of the polypeptide backbone for the bonds between N-Cα (called Phi, φ) and Cα-C (called Psi, ψ) and essentially gives a polypeptide conformational flexibility.

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25
Q

What is the alfa carbon in a peptide chain?

A

The alfa carbon is the carbon atom to which both the amino and carboxyl groups are covalently linked.

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26
Q

How do alfa helices form?

A

Helices are cylindrical arise as a result of energetically favorable local hydrogen bonding between atoms of the backbone of the protein chain (between main chain carbonyl group and amide group of another amino acid 4 residues away).

In stretches of of the chain with repetitive phi and psi values of around -60, -60, a right-handed helix is formed called the alfa helix.

The initiation barrier for this structure is low and the formation is fast.

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27
Q

How do beta sheets form?

A

Several polypeptide strands align with each other and permit energy-favorable hydrogen bonding.

A single chain is called a beta-strand and when a set of beta-strands hydrogen bonds together side by side a beta sheet is formed.

This secondary structure has a high initiation barrier and a slow formation.

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28
Q

Do the side chains interfere in a secondary structure of a protein?

A

No, the hydrogen bonds that form the secondary structures come from the backbone of the polypeptide chains.

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29
Q

What is a beta-turn?

A

A beta turn is a short regional where the protein chain changes direction 180 degrees. These are for example found between 2 beta strands.

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30
Q

what are loops?

A

The connecting pieces that allow helices and sheets to pack, creating the protein structure.

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31
Q

What is a Ramachandran plot?

A

The Ramachandran plot is a plot for the phi and psi values for all the residues of a protein structure. The values of the angles where most of the amino acids were found were calculated as well as the values where it is rare to find an amino acid.

These plots are useful tools to estimate how plausible a predicted secondary protein structure is or to predict a secondary structure.

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32
Q

Why are most of the dots in a Ramachandran plot in the same two squares?

A

Not all combinations of phi and psi are possible because of for example steric hindrance.

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33
Q

How do proteins find their structure?

A

Proteins obey the laws of thermodynamics: their structure must have the lowest free energy.

34
Q

What determines the tertiary structure?

A

The interactions between secondary structure elements (sheets and helices).

hydrophobic effect.

35
Q

Why do we rarely find charged residues on the inside of the tertiary structure?

A

Because charged residues are usually hydrophilic and will be located on the surface of the protein and form interactions with the water molecules.

They will also tend to be on the surface because there they can form ionic interactions with other residues and the solvent.

36
Q

Why is water important for protein folding?

A

Because the polar or charged residues will want to form interactions with the water and the non-polar residues will want to hide from the water and form interactions with other hydrophobic residues. This will lead to a folding of the protein where the hydrophobic residues are on the inside and the hydrophilic on the outside.

37
Q

What amino acids are lipophilic?

A

Those residues that are hydrophobic are also lipophilic.

38
Q

Why are prolines rare in helices? Where are they common?

A

Because they cannot form hydrogen bonds due to their bulky side-chain. It causes kinks on the helices which increases the risk for the helix to break.

They are instead common in turns.

39
Q

Why is glycine so flexible?

A

Because it has no side-chain and that means no clashes. Glycine is therefore flexible on the ramachandran map and are common in many structures.

40
Q

What kinds of interaction can we find in a tertiary structure?

A

Hydrogen bonds
Hydrophobic interactions - Van der Waal
Salt bridges
Disulfide bonds
Water

41
Q

A cystein residue in a protein was mutated to alanine. The mutant receptor was found to be more flexible, why?

A

cysteine creates covalent bonds to strengthen tertiary structures. Alanine does not create bonds as strong.

42
Q

It is four times more likely to find a phenylalanine in the interior of a protein compared to tyrosine. Why?

A

Because phenylalanine is hydrophobic and tyrosine is hydrophilic.

43
Q

How come cysteine makes proteins less flexible?

A

Because cysteine has a thiol (-SH) group on their side chain. The thiol group has an unpaired proton and will therefore form covalent bonds (disulfid bridges S-S) to other cysteines.

44
Q

What are the three main experimental methods for protein structure determination?

A

X-ray crystallography
NMR spectroscopy
3D electron microscopy

45
Q

How can X-ray crystallography determine protein structure?

A

The method is based on the law of diffraction.

A protein is purified and crystallized, then subjected to a beam of X-rays and from this a specific diffraction pattern can be seen.

From the diffraction pattern an electron density map is calculated and from this we can locate each atoms in the structure.

Proteins need to be able to form crystals for this method to work.

46
Q

What are the quality metrics for crystal structures?

A

Resolution: measures the amount of detail that can be seen in the experimental data. Measured in Ångström and a lower value means higher resolution.

R-value: Measures how well the atomic model is supported by the experimentally observed diffraction patterns (typical value around 0.2).

Resolution/R should be around 10.

47
Q

What is NMR spectroscopy?

A

The protein is purified and solved in liquid, placed in a strong magnetic field, and probed with radio waves.

We can then see how much nuclear magnetic resonances (energy) is released when the protein goes back to low energy state and it can give a list of atomic nuclei that are close to one another and characterize the local conformation of atoms that are bonded together.

The set of distances (restraints) between atoms is then use to build atomic level models of the protein.

Only works for very small and water soluble proteins

48
Q

Explain 3D electron microscopy/cryo EM

A

Suitable for large proteins and complexes (quaternary structures).

A solution of proteins in water that you freeze to ice crystals. We take pictures of the proteins in the ice structure and then use computational methods to find the overlapping structures to find the true structure of the protein.

The resolution of this method is not very high.

49
Q

What is ligand binding driven by?

A

Shape complementarity and polar interactions.

The ligand in the solution is pushed towards the active site because of electrostatic forces defined by Columbus law of physics (opposites attract).

50
Q

What is ligand recognition?

A

Ligand recognition is a specific form of molecular recognition where a part of a protein recognizes and binds a ligand. The ligands can range in size from a few atoms to whole other proteins.

key for protein function.

51
Q

What interactions are important in ligand recognition?

A

Hydrogen bonding

Hydrophobic interactions - often a major driving force of binding since binding affinities of ligands often correlate with buried binding sites - meaning that the strength of the bond is higher when the surface area is buried within the protein.

52
Q

Which are the three major protein classes? What functions do they have?

A

Fibrous proteins - Structural functions, building materials.

Globular proteins - “doer’s” transportation, regulation, enzymes ect.

Membrane proteins - receptors, channels, transporters on the cell surface.

53
Q

What are fibrous proteins? Give examples of fibrous proteins.

A

They are structural building blocks of for example hair, nails, claws ect.

Large, insoluble proteins with simple interactions and secondary structures.

Ex. Collagen, keratin

54
Q

What are globular proteins?

A

Globular proteins are more complex than fibrous proteins and have tertiary and quaternary structures. It is the most varied group of proteins.

They are spherical.

They are mostly enzymes and are soluble.

Can be easily determined with X-ray crystallography/NMR.

55
Q

What is the pKa value?

A

The pKa value is the dissociation constant meaning that it tells us wether the aa will donate or accept protons at certain pH-values.

The lower the pKa the more acidic the residue is. At pH values below the pKa the residue accepts protons and becomes less acidic. At pH above the pKa the residue gives away protons and becomes more acidic. Residues with low pKa is more likely to be deprotonated.

56
Q

Give an example of an amino acid with a charged side chain (at physiological pH) and an aa with an aromatic side chain.

What types of interactions can the side chain be involved in?

A

Charged: Lysine has a positive charge which means that it can form salt bridges with negatively charged amino acids. Lysine can also form hydrogen bonds.

Aromatic: Tyrosine has an aromatic ring and can for example form aromatic stackings with other aromatic rings.

57
Q

Give an example of one clearly hydrophobic and hydrophilic amino acid.

Where in globular and membrane proteins do you expect to find these two amino acids?

A

Hydrophobic: Alanine. This aa will likely be found on the inside of the structure of a globular protein and along the membrane of a membrane protein.

Hydrophilic: Serine. This aa will most likely be located on the surface of a globular protein and on the sides of the membrane of a membrane protein where the water is.

58
Q

Proline and cysteine have unique properties that can have strong influence on protein structure. Why?

A

The side-chain of proline is bonded to the backbone which makes it unable to move and the secondary structure protein will be less flexible.

Cysteine has a thiol group that can form disulfide bonds (S-S) that are covalent with other cysteines. This will make the tertiary structure of a protein less flexible.

59
Q

Give examples of what functions membrane proteins usually have.

A

Channels (ex. ion channels)
Transporters
Receptors
Enzymes

It is usually difficult to determine their structures experimentally.

60
Q

What are GPCRs?

A

G-protein coupled receptors. It’s an integral membrane protein that works as receptors and recognizes molecules on the outside of the cell and mediates signaling inside the cell which then give cell responses.

These are important because around 30% of all manufactured drugs bind to GPCRs. Ex. dopamine receptors, histamine receptors and opioid receptors.

61
Q

Explain why alpha-helices are polar.
Can these charges be neutralized? How?

A

The carbonyl groups (C=O= are pointed towards the C-terminal making it more negative. And the amide groups are doing the opposite creating a polar structure.

The charge of the helix can be neutralized by capping residues on the ends of the helix. On the negative side there can be a positively charged residue and on the positive side there can be a negative residue.

62
Q

Describe the main-chain hydrogen-bonding pattern in an α-helix.

A

The oxygen on the carbonyl group on one residue bonds with the hydrogen on the amide group 4 residues away.

63
Q

What does the RMS value tell us?

A

Root Mean Square value.

In the case of proteins, it is often used to assess the similarity or deviation of different protein structures. A lower RMSD value indicates a closer match between the structures.

64
Q

You are a scientist studying the function of neuroglobin. You want to know how its structure compares to structures of myoglobin and hemoglobin. You have access to the pdb file and to a computer running PyMOL.

What would you do?

A

Align the proteins in PyMOL and look at the RMS value. A small value would indicate that the structures are similar.

65
Q

Describe for what type of analysis the following display options are useful:

a) all-atom representation (“lines” or “sticks”)

b) cartoon representation

c) space-filling (“spheres”) or surface representation

A

a) To see interaction and their patterns very specific. Good way to view the primary structure.

b) To see the secondary and tertiary structures.

c) To see the size of atoms and how much space they take in the structure. Also to look at a single unlinked atom.

66
Q

Does the side chains influence the secondary structure?

A

No. Because the fold of the protein is decided by the backbone of the secondary structure.

The side chains interact with each other and influence the tertiary structure.

67
Q

What is the distance of carbon-carbon bonds?

A

1.5Å. That is also the smallest distance we can see with X-ray crystallography.

68
Q

Why can “flips” be necessary when validating a structure that you got from crystallography?

A

Crystallography makes the structure prediction based on the electron denisity map that you get when shooting a crystal with x-rays.

Some atoms (O,N and C) have a similar size and the electron density will leave the same mark for all these atoms.

To optimize hydrogen bonding when validating the structure we can flip those parts of the structure.

This applies to the side chains that has these atoms (histidine, glutamine and asparagine).

69
Q

What does clashing mean in the context of structure prediction?

A

Clashes mean that side chains that would normally resell each other are too close in the structure. It means that the prediction is not optimal.

70
Q

Why does proline and glycine has separate plots in ramachandran analysis?

A

Because the side chains of these has special qualities that makes the rules for how the backbone form secondary structures different.

Proline is very fixed and glycine is very flexible.

71
Q

How could it be that when you look at the electron density around a structure that some side chains might look like they don’t have any electrons around them?

Does this meant that the structure prediction is wrong?

A

Because the regions of a protein structure that are exposed to solve move around are hard to crystallize. It does not have to mean that the prediction is wrong.

72
Q

What is the maximum length of a hydrogen bond?

A

3.5Å

73
Q

Define what a salt bridge looks like.

A

A polar interaction between two charged residues. COO- from one residue with a charged nitrogen (H3N) from another residue.

74
Q

What is an okay distance for aromatic interaction?

A

Below 6Å

75
Q

Is it more likely to find histidine on the surface or on the inside of a protein structure?

A

Both because it is neutral at physiological pH.

76
Q

What are the limitations of X-ray crystallography?

A

Can only be used for proteins that have crystal structures.

The electron density maps for atoms of the same size (N, O, C) might need to be flipped because it doesn’t know which atoms should actually be there and that might lead to unfavorable hydrogen bonding in structure predictions.

77
Q

Which are the aromatic residues?

A

Tryptophan
Tyrosine
Phenylalanine

78
Q

Give examples of two residues that can form hydrogen bonds.

A

Hydrogen bonds are more likely to be formed by polar residues to their electronegative atoms.

79
Q

Which amino acid is the most hydrophobic and the most hydrophilic?

A

Hydrophobic: Isoleucine
Hydrophilic: Arginine

80
Q

What happens to a charged amino acid if the pH of the solvent is below vs. above the pKa value?

A

If the pH is above the pka then the amino acid will get deprotonated. Positive charges become neutral and negative charges get more negative.

If the pH is below the pka then the amino acid gets protonated. Negative charges become neutral and positive charges become more positive.

period 2 (6 decks)

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