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bioc2004 ch > 3. Protein Energetics & Folding > Flashcards

3. Protein Energetics & Folding Flashcards

1
Q

What is allostery?

A

The process by which macromolecules transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity

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2
Q

What are the molecular forces?

A

Covalent bonds - bonds between AA or within an AA

Non-covalent interactions - local/long range interactions at sequence level

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3
Q

What equation does the covalent bond length obey?

A

Hooke’s law: F = Kb.s

F = force
Kb = bond constant 
s = bond length
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4
Q

What is the equation for energy compared to bond length?

A

E = 0.5Kb(b-b0)^2

b =
b0 =
Kb = force constant

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5
Q

What is the optimum bond length?

A

The sum of the bonding radii

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6
Q

What is the difference between sp2 and sp3 hybridisation?

A

Sp3 = 4 single bonds bound to one carbon - tetrahedral, 109.5deg.

sp2 = double bon between carbons, 120deg.

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7
Q

What is the equation for the optimum energy bond angle

A

E = 0.5K(theta)((theta)-(theta)0)^2

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8
Q

How many atoms define the torso angle?

A

4

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9
Q

What is the favoured torsion angle conformation?

A

Staggered (not eclipsed) due to steric effect - energy form will penalise deviation from staggered

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10
Q

What 3 types of non-covalent interactions occur between atoms?

A
  • Electrostatic
  • Van Der Waals
  • Hydrogen bonds
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11
Q

What is the electrostatic interaction?

A

Interactions between charged atoms, like charges repel (and vice versa)

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12
Q

What is coulombs law?

A

E = (qi)(qj)/4(pi)(epsilon0)(r^2)

qi = charge on atom i 
qp = charge on atom j 
epsilon0 = permittivity of space/dielectric constant 
r = distance between atoms
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13
Q

What does coulombs law assume? What is replaced to improve this?

A

Assumes a vacuum. epsilonR.r replaces r^2.

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14
Q

What type of forces are VDW?

A

Repulsive AND attractive

Repulsive: electron-electron interaction (short range)

Attractive: induced dipole/induced dipole (longer range) - atom 1 has spontaneous dipole which induces dipole in atom 2

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15
Q

Where is the sum of VDW radii present on an energy-distance graph? What equation defines this energy?

A

At a low energy trough

E = Aij/(r^12) - Bij/(r^6)

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16
Q

Define hydrogen bonds

A

Interaction between hydrogen bound to an electronegative atom (e.g. N or O), interaction of charges, directional

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17
Q

When calculating a simulation, what are covalent and non-covalent bonds assumed to be?

A

Covalent - local

Non-covalent - distant

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18
Q

What are the benefits of using a cutoff in protein folding simulations?

A

Saves time as you do not have to calculate interactions between atoms further apart then a certain distance

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19
Q

What three cutoff methods are there? Describe each

A

Truncation - interactions set to 0 for distances greater than cutoff value

Shift - change the whole potential energy surface so that E = 0 at cutoff value

Switch - tapers over a range of distances

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20
Q

What important equation forms the basis of folding simulations?

A

Time -proportional to- N^2

N = number of particles

This may not be right but my notes are bad

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21
Q

What law does molecular dynamics rely on?

A

Newton’s second = F = ma

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22
Q

What is molecular dynamics?

A

A computer simulation method for studying the physical movements of atoms

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23
Q

What is the process used when studying the physical moments of atoms using molecular dynamics?

A
  1. Give atoms initial positions r^(t=0), v = 0, a = 0, i = 0
  2. Assign each atom a random velocity (Boltzmann relates to temp.) and calculate the force and then acceleration from this
  3. Now you have acceleration, move the atoms
  4. Move time forward by deltaT (small T)
  5. Repeat from 2. for the time length you require
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24
Q

What equation is used to calculate the movement of atoms in molecular dynamics?

A

r^(i+1) = r^i + v^i + 0.5a(deltaT^2) +…

r^(i+1) = position at i+1
r^i = position at i 
v = velocity 
a = acceleration
deltaT = change in time
25
Q

What is the Verlet/Leapfrog algorithm?

A

An algorithm where you define the velocities of the molecule at the mid point of the intervals rather than taking the velocity at the start of time

26
Q

What are periodic boundaries? What is their benefit?

A

A set of boundary conditions used for approximating a large system by using a small part (unit cell)

Enable simulation to be performed using a small number of particles so less time is wasted calculating movement of water (water vastly outnumbers interesting particles)

27
Q

What is Hydrophobicity? What is it a result of?

A

An entropic effect of non polar substance aggregating in an aqueous solution, excluding water

28
Q

How is hydrophobicity a negative entropic effect?

A
  • H-bonds between water molecules are disrupted
  • H-bonds then orientate themselves tangentially to h’phobic surface foreign a cage
  • As such the water molecules lose translational and rotational energy
29
Q

What are the 4 hydrophobicity scales?

A

Quantification of hydrophobicity:

  1. Partitioning methods -
  2. Accessibly surface area methods - observe protein structure
  3. Chromatographic methods - reserved phase liquid chromatography (use non-polar stationery phase, polar mobile phase)
  4. Physical property methods - partial molar heat capacity, transition/surface temperature
30
Q

What are the four inter-molecular forces?

A

Same as intra-…

  • Electrostatics
  • Hydrogen bonding
  • Van der Waals
  • Hydrophobic effect
31
Q

What types of complementarity are important in protein-protein interactions? What fills the holes?

A

Charge and surface complementarity.

Water molecules (aka my tears)

32
Q

What is computational docking? What are the problems?

A

Something which predicts the orientation of one molecule to another when bound in stable complex.

  • Search space
  • flexibility
  • hydrophobicity

Make of those words what you will. I have made nothing from them.

33
Q

What may computational docking be effective for? Give examples of programs which do this.

A

Small molecules

GRID, DOCK, AUTODOCK

34
Q

What are amyloid plagues?

A

Insoluble fibrils composed of misfolded proteins which aggregate and form deposits (these fuck shit up)

35
Q

There are many ways for proteins to misfold, which way typically leads to production of amyloid fibrils?

A

Unfolded protein partially folds forming some secondary structure, but does not complete folding, the incomplete folded proteins are known as pre fibrillar species. These then aggregate to form amyloid fibrils

36
Q

What protein misfolding causes Sickle cell anaemia? how?

A

Haemoglobin E6V

Aggregate protein fibre formed which changes the shape of the RBCs causing them to become sickle shaped which may clog blood vessels.

37
Q

What is the role of p53? What happens if it becomes damaged?

A

GUARDIAN OF THE GENOME

  • recognises when DNA is damaged and slows down cell cycle to allow enzymatic repair
  • may also trigger apoptosis if necessary
  • misfolding of p53 can result in reduction in activity, this then allows DNA mutations to accumulate
  • this is not good
  • one might go as far as to say this is bad
38
Q

What four things does the hydrophobic effect depend on?

A
  • Solvent
  • Salt concentration
  • pH
  • Temperature
39
Q

What are IDPs? What AA are common in IDPs?

A

Intrinsically disordered proteins - do not have single unique structure

Polar and charged AA more common

40
Q

What is the entropy like in an IDP?

A

high

41
Q

What is the role of IDPs?

A

Regulation. Made more effective by ability to bind to multiple ligands

42
Q

Who realised the problems of protein folding? What’s the paradox called?

A

Linus Pauling - basically for too many conformations to randomly fold

THE LEVINTHAL PARADOX - too many conformations, too little time

43
Q

How long does it take for a protein to fold usually?

A

ms

44
Q

What are the 2 protein folding methods? Describe each one

A

Diffusion-collision model: Nucleus formed, then 2ndary structure, 2ndary structures collide and pack to form native structure

Nucleation-condensation model:
2ndary and 3rdary structures made at same time to form native structure

45
Q

What is co-translational folding?

A

The N-temrinus of the protein begins to fold as the C-terminus is being synthesised

46
Q

What three experimental techniques may be used to observe protein folding? Describe how each one works

A
  • NMR - monitor H-D exchange in amide backbone of proteins e.g. CylR2
  • Circular Dichroism - use circularly polarised light, alpha helices/beta sheets absorb in different ways
  • Optical Tweezers - pull protein apart and visualise
47
Q

What causes the differential absorption of alpha helices/beta sheets in circular dichroism?

A

The hydrogen bonds of alpha helices occur between the residues in the helix whereas hydrogen bonding occurs between the sheets in beta sheets

48
Q

Which secondary structure forms first alpha helices or beta sheets?

A

Alpha helices because they are internal stabilised

49
Q

Describe how optical tweezers work

A
  • Glass beads links to protein via DNA linker (to cysteine)
  • Focus beam of light onto glass which you can use to move the class beads
  • View protein from above and pull the protein apart
  • then measure strength required to pull apart as well as how it looks as it is being pulled apart
50
Q

Describe the molten globule

A

Compact and has secondary structure but the intricacies of tertiary structure are missing and the h’phobic core is loose

51
Q

Describe the energy landscape of the protein folding

A

Global and local minima and other shit

52
Q

How does the entropy and enthalpy vary as the protein folds?

A

Entropy is reduced, enthalpy increases

53
Q

What is the molten globule?

A

Folding intermediate or trapped state -

54
Q

Why can’t we simulate protein folding?

A
  • Inaccuracy of force field
  • Huge amount of conformational space to explore
  • Can’t simulate hydrophobic effect
55
Q

Can we unfold a protein using a simulation? How?

A

Yes, using simulation optical tweezers

56
Q

What is the lattice model of folding?

A

A simplified model of protein folding used in simulations.

  • Each AA simulated as single bead on grid
  • each bead has types (usually HP - hydrophobic and polar)
  • make cubic attic and give each AA a grid point
  • adjacent residues in the primary sequence have to sit in adjacent places on grid
  • Energy function describes interactions of neighbouring beads
57
Q

Describe the process by which Dna-x aid folding with GroEL/ES

A
  1. Dna-K binds to protein 2.Dna-J binds to Dna-K-portein complex
  2. GroEL/ES binds, removing Dna-K-Dna-J from protein
  3. Protein becomes folded and GroEL/ES leave
58
Q

Tell us your most interesting chaperone facts :)

A
  • main function - prevent protein aggregation
  • contain doughnut shaped holes which keep molecules away from others (thus preventing aggregation)
  • mammalian and bacterial chaperone proteins are different

bioc2004 ch (11 decks)

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