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MCP Unit 2 > Proteins > Flashcards

Proteins Flashcards

1
Q

why study proteins

A
  • everything in body is either a protein or made by one
  • proteins catalyze every process in cell
  • genetic diseases caused by proteins
  • infectious diseases dependent on proteins
  • targets of drugs
  • transmit info
  • antibodies protect
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2
Q

functions of proteins determined by

A
  • polymer length

- aa composition

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3
Q

molecular medicine

A
  • can’t go directly from genes to disease and treatment yet
  • need to go through aa sequence, protein structure to find function, which can lead to cause of disease, drug design, and prevention to understand disease and treatment
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4
Q

proteome

A

-content of proteins within the cell at any given time (more complex than the genome)

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5
Q

Tipranivir

A
  • prescribed anti-HIV drug
  • Asp26 (one from each monomer) are residues responsible for nuclephilic attack on the substrate
  • non hydrolyzable
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6
Q

alzheimers

A
  • characterized by extensive deposits of misfolded proteins (amyloid fibers) in the brain
  • associated with cell death and loss of brain function
  • main component of these is a 42-residue fragment from the Alzheimer precursor protein (APP)
  • APP is normally cleaved to a 40-residue fragment
  • two extra AA enough to convert normal soluble protein to a sticky peptide that builds up in the brain
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7
Q

Concepts from lecture

A
  • proteins are the only polymers that spontaneously fold from an unstructured noodle to a specific 3D shape (except RNA- but not nearly as many structures)
  • the only thing different about the noodle and 3D shape is bond angles
  • patterns of atomic bumping in polypeptides favor certain combinations of bond rotations and prohibit others
  • allowed and disallowed bond angles determine types of structure that can form
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8
Q

protein structure

A

-not rocks, quite unstable (deltaG=0-10kcal/mol)
-constantly fold and unfold
-up to ~40% contain regions on intrinsic disorder
-many diseases caused by improper folding or degradation
-

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9
Q

phi and psi 1

A
  • each peptide has phi,psi angle combo
  • determine twists and turns chains take
  • alpha helix (or beta sheet) residues have similar phi, psi combos
  • alpha closer to 0-scrunched
  • beta closer to 180- almost fully extended
  • angle seen between atoms when sighting down central bond psi=carbon-carbon, phi=carbon-nitrogen
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10
Q

Ramachandran plot

A
  • plot of allowed angles of phi and psi
  • only a small fraction allowed (dark grey)
  • only allows certain structures to form
  • plots arise simply from how atoms are connected (bond length, angle, and hard-sphere repulsions
  • glycine is a BAMF-more options
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11
Q

properties of amino acids

A
  • hydrophobic
  • hydrophilic
  • unique (pro, gly, cys)
  • protein structure can be understood by the binary code of polar on the outside, polar on the inside
  • function in many instances boils down to a few amino acids
  • amino acid substitutions are common, effect can be significant or not
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12
Q

Asp pKa

A

4

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13
Q

Glu pKa

A

4

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14
Q

His pKa

A

6.5

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15
Q

Cys pKa

A

8.5

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16
Q

Lys pKa

A

10

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17
Q

Arg pKa

A

12

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18
Q

carboxy terminus pKa

A

4

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19
Q

amino terminus pKa

A

8

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20
Q

hydrophobic-aliphatic (most)

A
  • alanine
  • valine
  • leucine
  • isoleu
  • proline
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21
Q

aromatic, sulfur containing side chains, less hydrophobic

A
  • phenylalanine
  • tyrosine
  • tryptophan
  • methionine
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22
Q

pKa and ionization

A
  • acid dissociation constant
  • low pKa=acidic, binds H loosely
  • high pKa=basic, binds h tightly
  • pKa is pH at which half the ionizing groups are protonated, half are deprotonated
  • pHpKa, low H in solution, draws off H
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23
Q

pKa cont

A

if pKa of group is 4, at pH 7 will be deprotonated (because likes to be proton donor (acid) and there aren’t that many around). at pH 3, will be protonated because there are lots of protons around
-if pH is 4, half the groups would be protonated and half wouldn’t be

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24
Q

negatively charged side chains (at pH7)

A

pKa’s low- like to give protons up (at pH7), acidic, only protonated at pHs lower than pKa

  • aspartic acid
  • glutamic acid
  • cysteine (pKa 8.5, but sulfur likes to give H to form SS bonds)
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25
Q

positively charged side chains (at pH7)

A
  • pKas high, like to keep protons (at pH7), only deprotonated at pHs higher than pKa
  • histidine
  • lysine
  • arginine
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26
Q

histidine

A
  • can accept and donate protons at physiological pH
  • only molecule that ionizes near physiological pH
  • used as catalytic residue by enzymes in acid-base catalysis
  • 5 membered ring is imidazole ring
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27
Q

structure can be used to change pKa (Asp)

A
  • local environment can lower or raise pKa by >4 units
  • very important for enzymes
  • Asp is neg at physiological pH
  • adding excess H will put it back on- enough so that pH is 4
  • if Asp is near pos AA, really wants to give up its H, pKa decreases (becomes more acidic, binds H looser)
  • if Asp near neg AA, keep its H more than usual, pKa increases, becomes less acidic, binds H tighter
  • same if its near a greasy blob
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28
Q

polar uncharged side chains-hydroxyl

A
  • pKa-16-keeps its H except in extreme conditions
  • serine
  • threonine
  • electronegative atoms
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29
Q

polar uncharged side chains-amide

A
  • asparagine
  • glutamine
  • electronegative atoms
  • more hydrophilic than ser or thr
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30
Q

unique side chains

A
  • Glycine-lack of side chain-flexible
  • Proline-cis peptide bond favors kinks, turns. no H-bond donor on peptide bond
  • Cysteine-thiol group can oxidize to SS
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31
Q

covalent properties of polypeptides

A

Backbone:

  • properties are dominated by the peptide bond
  • simple bonding and steric considerations encourage formation of certain types of structures
  • peptide groups are necessary for 3D structure, but not sufficient

AA side chains

  • gives proteins their individuality
  • chemical interactions and shape of side chains determine structure

*3D structure cannot be predicted by AA chain alone

32
Q

protein folding

A
  • non-covalent interactions
  • well folded is only 5-15 kcal/mol more stable than unfolded (2-3 kcal/mol)
  • structure is dynamic
  • bond rotations is how it folds
  • accumulation of small favorable non-covalents that overcome unfavorable loss of rotational entropy

Forces:

  • electrostatic
  • dipolar-salt bridges and other interactions
  • hydrogen bonding
  • van der waals
  • hydrophobic effect
33
Q

Electrostatic interactions

A
  • all follow coulomb’s law (e=q1q2/r^2D)
  • D is dielectric constant-polarity of local environment-vacuum is 1 water is 80
  • salt bridges and other interactions
  • maximize charge-charge and charge-water interactions
  • ion pairs, Asp, Glu, Lys, Arg and His often found on protein surface-solubility of globular proteins in water
  • charged groups rarely on interior
  • ion pairs also help in DNA binding proteins, provide counter charge to substrate to help binding
34
Q

salt bridges

A
  • strongest electrostatic forces
  • frequently observed on protein surfaces
  • rarely seen in interior
35
Q

buried charge

A
  • rhodopsin

- only Lys residue in transmembrane helices, forms Schiff base with the chromophore, 11-cis retinal

36
Q

ATP synthase and buried charge

A
  • F0 proton channel in ATP synthase- proton translocation channel is formed by helical subunits that sits in the membrane and rotates.
  • helices non-polar except single Glu-proton binds Glu and rides like merry go round
  • kink in helix by Pro residue three positions down from Gly
37
Q

Dipolar interactions-weak electrostatic

A
  • 2 charges separated by distance
  • dipole arises from difference in electronegativity
  • no net charge on molecule
  • dipole moment- mu-(excess charge) X (separation)
  • partial positive and negative without formal net charge
  • electronegative atoms responsible
  • common is peptide bond
  • antiparallel arrangement is energetically favorable
  • occurs in beta sheets
  • alpha helices are parallel-offset by charged side chains
38
Q

hydrogen bonding

A
  • special electrostatic interaction
  • 2 electronegative atoms compete for same H
  • oxygen, nitrogen, sulfur
  • in proteins, all donors are bonded to acceptors and vise versa
  • strong because of coulombs law- peptide carboxylate (full charge) strongest
  • straight stronger than kinked
  • can also occur b/n charged groups
39
Q

proteins as polymers

A
  • compact 3D shape
  • specific function
  • highly efficient
  • folds on its own
  • other polymers do not fold
40
Q

amino acids

A
  • building blocks
  • alpha carbon-amino,cooh, and side chain
  • central carbon is chiral but only L enantiomer synthesized and incorporated into proteins
41
Q

peptide bond

A
  • planar (no rot around DB) and trans (steric clash)
  • two resonance forms
  • 60% left (DB O) 40% right (DB N)
  • C-N bond 40% DB character
  • rotations about the bonds to and from the central carbon
42
Q

planarity

A
  • reduces bond rotations
  • two rotatable bonds per residue
  • rotatable bonds define backbone and are called phi (C-C) and psi (C-N)
  • look at pictures for phi and psi
43
Q

phi and psi 2

A
  • tell us about conformation of polypeptide backbone
  • only 10-20% of allowed conformations are found in nature
  • rotatable bonds
  • 180- extended conformation
  • 0-compaction
44
Q

van der Waals forces

A
  • mutually induced dipole (transient)
  • present between all atoms
  • net energy bonus as a result of favorable electrostatic interactions
  • approximated by lennard-jones potential
  • proteins fold to maximize van der Waals energy (tightly packed cores)
  • optimal distances in core for maximum interactions
  • no empty space
45
Q

hydrophobic effect

A
  • principle glue that holds proteins together
  • major DF for interactions with hormones, nucleic acids, and other proteins
  • tendency of certain molecules to interact with themselves and not with water
  • non-polar/hydrophobic groups
  • lack charges, dipoles, polar groups, and H bonding groups
46
Q

hydrophobic effect and water

A
  • hydrophobic molecules do not have attraction for themselves or repulsion for water-hydrophobic effect is due to water
  • water has unusually high attraction for itself due to polarity and H-bonding properties (donor and acceptor)
  • non-polar groups can’t H bond, and to make up for this, water changes its structure in the vicinity of dissolved hydrophobic molecules
  • structure is called clathrates-ice like
  • energetically unfavorable and origin of effect
47
Q

clathrates

A
  • when non-polar molecules and water interact (in aq solns), water forms highly ordered structures around the molecule
  • form H bonded icebergs around the non-polar surface
  • decrease in entropy (can rotate more freely in bulk) is responsible for the tendency of non-polar molecules to cluster together, reducing non-polar surface exposed to water
48
Q

secondary structure

A
  • alpha helix, beta sheets, beta turns
  • short, simple, repeating
  • stabilized by interactions between residues close in sequence
  • can occur in short peptides
49
Q

tertiary structure

A
  • longer polypeptides associate with one another to form these
  • overall 3D conformation
  • stabilized by short range as well as long range contact between residues distant in sequence
  • usually required for the protein to function although not often sufficient (need quaternary)
50
Q

quaternary structure

A
  • two or more individual subunits that function as a whole

- all foldings are stabilized by electrostatic, h bonding, vdF and hydrophobic

51
Q

alpha helix

A
  • most frequently observed
  • average protein contains 31% helix
  • characterized by specific H bonding patters between the peptide NH of i and the peptide CO of i+4
  • peptide backbone coils to make a rod, the side chains stick out
  • side chains tilted toward N terminus-can’t rotate freely
  • periodicity of 3.6 residues
  • chains of every 4th residue lie on approx the same face of the helix
  • 5.4 angstroms per turn
  • average 12 residues long
52
Q

3.6 residue repeat

A
  • favorable backbone dihedral angles
  • near optimal H bond geometry
  • good VdW contacts between backbone atoms
  • other types of helices possible but uncommon
53
Q

stabilization of alpha helix

A
  • backbone-backbone
  • backbone-side chain
  • side chain-side chain
54
Q

backbone- backbone interactions in alpha helix

A
  • extensive network of NH and CO bonds formed b/n peptide groups 4 residues apart
  • H bonds have optimal geo and aligned parallel to helix axis
  • tightly packed, good VdW
55
Q

backbone-side chain interactions in alpha helix

A
  • peptide bonds have polarity
  • 0.4 e units of pos on N and neg on COOh
  • results in permanent dipole
  • all aligned and form macro-dipole
  • therefore overall pos at N terminus and overall neg on C terminus
  • place corresponding residues near termini to stabilize helix
56
Q

side chain-side chain interactions in alpha helix

A
  • 3.6 residue repeat means side chains of i and i+4 are closest
  • in contact with each other via H bonds, electrostatic, hydrophobic, and VdW
57
Q

helix former AA

A
  • alanine

- no side chain means default backbone conformation is helical

58
Q

strong helix breakers

A
  • Proline-no NH to H bond

- Glycine-flexible

59
Q

medium helix breakers

A
  • beta branched or bulky
  • Valine
  • Threonine
  • Tryptophan
  • Phenylalanine
  • lose much rotational freedom (entropy) in helix
60
Q

helix indifferent

A
  • long, straight chains
  • arginine
  • lysine
  • glutamate
  • lose less rotational freedom (Alanin loses none)
61
Q

Myoglobin (and other alpha helices)

A
  • one side of helix usually faces in and the other faces out (non-polar and polar)
  • tightly associated with cell membranes
  • membrane anchors consist of several helices containing mostly non-polar residues-interact with interior of lipid bilayer
  • disrupted by detergents
62
Q

beta sheets

A
  • average protein contains 28% beta sheets
  • made up of two or more beta strands
  • polypeptide chain is straight and nearly completely extended
  • H bonds are formed between peptide groups of each strand
  • pleated appearance
  • parallel or antiparallel
  • parallel H bonds slightly bent, so antiparallel more likely
63
Q

why beta sheets?

A
  • favorable backbone dihedral angles
  • phi,psi is about 140 degrees, chain is nearly fully extended
  • rise is 3.5 angstroms
  • periodicity is 2-side chains are 2 apart
  • straight H bonds between strands
  • interaction between adjacent strands is tertiary and called amyloid
  • pattern of hydrophobic amino acids stabilizes
  • frequently amphipathic
64
Q

interconversion between helices and sheets

A
  • polypeptides can form both
  • implicated in disease
  • myoglobin- can form amyloid- which causes disease
65
Q

reverse beta turn

A
  • 1/4 of protein structure
  • several types
  • much sequence variability
  • glycine required-relieves steric clashes
  • proline preferred-covalent bondbetween the side chain and main chain puts a kink in the backgone
  • other positions are solvent exposed and polar residues
  • polypeptide has to reverse directions in a globular protein
  • tight turns-3-4 residues
  • stabilized by H bonding
66
Q

irregular protein structure

A
  • random coil- but not truly random-wouldn’t crystallize
  • generally only random in the sense that it is not periodic
  • usually has specific structure
  • surface loops are critical to function
  • loops give proteins individuality
  • found on protein surface and are comprised of mostly hydrophilic residues
  • flexible and tether globular domains together
  • frequently form the binding site with another protein or substrate
67
Q

protein loop

A
  • stretch of polypeptide that is neither alpha helix, beta sheet, of reverse turn
  • lack regular H bonded conformation and are not secondary structure
68
Q

motifs

A
  • small functional units that are part of larger structures
  • short stretches of secondary structures
  • not usually stable by themselves
  • used in molecular recognition
  • helix turn helix
69
Q

helix turn helix

A
  • proteins recognize specific sequences of DNA
  • found in all kingdoms of life
  • recognition alpha helix and a support alpha helix, connected by a turn
  • recognition helix sits in major groove of DNA and binds to specific sequences of nucleotides
  • structure of recognition helix maintained by side chain-side chain contacts between it and the support helix
  • helices held together by a small hydrophobic core consisting of non-polar side chains
  • i,i+3(4) spacing of hydrophobic residues make sure the HTH fold is achieved
70
Q

zinc finger

A
  • cysteins and histines
  • binds DNA weakly
  • TF proteins use 2-40 repeats (of zinc finger chain) to bind DNA
71
Q

domains

A
  • stable, semi independent units of structure
  • residues within the domain interact more with each other than with the residues outside of it
  • stable in isolation
  • continuous stretches of polypeptide that are linked together by flexible loops, making it east to identify them
72
Q

coiled coil domain

A
  • extremely stable
  • fibrous proteins and TFs
  • heptad repeat
  • a-f
  • hydrophobic at a and d (1 and 4)
  • e and g usually opposite charge than a and d (5 and 7)
  • interact in helical wheel projection
  • a and d are hydrophobic glue
  • e and g provide electrostatic interactions
  • DNA binding, protein-protein recognition, mechanical orce transductions, viral penetration
  • hemagglutin
73
Q

GCN4

A
  • DNA binding domain is coiled coil
  • stabilizing half has heptad repeats
  • binding part is only helical and stable when bound
  • intrinsically disordered
  • see slide on pg 153
74
Q

hemagglutin

A
  • stalk domain is triple-stranded coiled coil
  • H=hemagglutin, N=neraminidase- account for differences in flu
  • Spanish flu was hybrid from recombination of 2 or more
  • HA is molecular harpoon
  • Flu enters, binds to cells via head domain of HA. endocytosed into cell (in capsule), when pH hits 5 from proton pumps, conformation change-extended loop folds to alpha helix
  • loop in tail domain and links tops of coiled coil helices to shorter alpha helices near bottom of coiled coil helices-coiled coil lengthens
  • head domain splays open, newly lengthened coiled coil thrust out and penetrate vacuolar membrane (tip is hydrophobic)
  • fusion of two membranes
  • similar to HIV (receptor binding), SARS, ebola
  • protein drugs don’t work well because they are degraded-D peptide can bind tighter and has longer life
  • look at picture for HIV
75
Q

pore-forming proteins

A
  • small (<50kD)
  • self associate and insert into PM of host
  • pokes a hole, causes leakage and cell death
  • anthrax, pneumonia, meningitis, cholera
  • alpha hemolysin
  • hydrophobic/philic interactions shape structure and function

MCP Unit 2 (10 decks)

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