MCB 102 Lec 4 Protein structure

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  1. What are the 4 levels of protein structure?
    • Primary: Amino acid residues
    • Secondary: α-helix/β sheets
    • Tertiary: Polypeptide chain
    • Quaternary: Assembled subunits
  2. Protein molecule adopt what specific conformation, unlike most organic polymers?
    Three-dimensional conformation
  3. The three-dimensional conformation is key to what in a protein?
    The ability of protein to fulfill a specific biological function
  4. What is this three-dimensional conformation called where protein has activity?
    Native fold
  5. What exists in large numbers within the native fold of a protein?
    Favorable interactions
  6. What happens to entropy when folding the protein into one specific native fold?
    • When unfolded, there's high entropy b/c there are many states it can possibly be in
    • Once it settles into one state, it drops in entropy
    • There is a cost in conformational entropy
  7. What bonds stabilize the folding of proteins?
    Disulfide bonds between cysteine amino acids
  8. Which level of protein structure determines the 3D structure?
    Primary sequence
  9. Which experiment proved that all that is needed to make a functional 3D protein is contained in the primary sequence?
    Afinsen Experiment (1973)
  10. What was the Afinsen Experiment?
    • Took a folded protein
    • Denatured it with urea and β-mercaptoethanol → unfolded and inactive
    • Rapidly diluted urea and β-mercap → got scrambled protein, incorrectly folded and inactive
    • Slow dialysis/dilution → Renatured protein, properly folded and fully active
  11. What did teh Afinsen Experiment prove?
    All that is needed to make a fully functional 3D protein is present in the primary sequence
  12. Which of the 4 levels of protein structures can be predicted based on the primary sequence?
    • Secondary structure- α helices and β sheets
    • But not tertiary structure
  13. How do we know cysteines aren't solely responsible for the specific pattern of folding?
    • Cysteines are likely to make disulfide bonds
    • But could make them wrong, with the wrong combinations
  14. What predicts the specific pattern of folding of proteins into the secondary structure?
    Specific amino acid sequences
  15. What are the forces involved in the unfolded protein state?
    • More H bonds with water, less with self (overall number of H bonds probably similar to folded)
    • Salt bridges with itself in an environment of higher dielectric constant (weaker bonds, higher enthalpy)
    • Exposes more hydrophobic residues to water (less entropically favored)
    • Van der walls interactions present
  16. What are the forces involved in the folded protein state?
    • More H bonds with itself, less with water (enthalpy doesn't change much, but increased entropy in water b/c free water molecules)
    • Salt bridges with itself in an environment with a lower dielectric constant (stronger bonds, lower enthalpy)
    • Less hydrophobic groups exposed (hydrophobic packing, more free water, entropically favored)
    • Van der walls interactions present
  17. What are salt bridges?
    Interactions between water and charged group
  18. How do salt bridges affect interactions between the groups of the protein?
    • Water weakens interactions between charged groups
    • Positive and negative charges interact with water instead of with each other
  19. What does high dielectric constant mean?
    Substances that interfere with charges more
  20. What is the difference in bond strength between charged groups due to salt bridges in an environment with a lower dielectric constant vs. a higher dielectric constant?
    • Higher dielectric constant- Salt bridges form stronger, more stable bonds btwn dielectric substance and charged group
    • Lower dielectric constant- Salt bridges form weaker bonds btwn dielectric substance and charged group
  21. What kind of bond properties partially dictates the stucture of the protein?
    Properties of peptide bonds
  22. What is tautomerization in a peptide bond?
    • Peptide bond has ability to resonate
    • Resonance of the lone pair from the amide nitrogen to the carbonyl oxygen allows for greater electron delocalization
  23. What about the peptide bond results a partion double bond nature?
    Tautomerization
  24. What does tautomerization of peptide bonds result in?
    • Planarity: Due to partial double bond nature of amide C-N linkage
    • Formation of partial dipole moment: Due to charge separation
  25. How does the partial double bond nature of peptides affect structure?
    • Doesn't allow roation around C-N bond
    • Planarity
  26. In peptides, we find that R chains of two contiguous amino acids are usually in what kind of configuration?
    Trans
  27. Why are R chains of two contiguous amino acids in a peptide usually in trans configuration?
    To avoid steric clashing from cis configuration, das not favored
  28. What's the exception for steric clashing in peptide structure?
    • Proline
    • Clashes/uncomfortable either way
    • No strong preference between cis and trans
  29. A polypeptide is made up of a series of _____ liked at α-carbons
    planes
  30. How many bonds separate sequential α-carbons in a polypeptide chain?
    3
  31. Which bonds can rotate in a polypeptide chain?
    • N-αC
    • αC-C
  32. What are the names of the angles that describe the rotation of dihedral angles in polypeptides?
    • phi (Φ) = N-αC
    • psi (ψ) = αC-N
  33. What are dihedral angles?
    Angles between planes
  34. Why would any bond, other than the N-C peptide bond, be rotationally hindered?
    • Depends on the size and charge of the R groups
    • Some combinations of phi and psi are favorable, while others are not b/c of steric crowding of backbone atoms with other atoms in the backbone or side chains
  35. What are the angles of phi and psi for a fully extended polypeptide?
    180°
  36. What does a ramachandran plot show?
    • The distribution of phi and psi, dihedral angles that are found in a protein
    • Common secondary structure elements
    • Reveals regions with unusual backbone structure
  37. Primary structure dictates which other levels of protein structure?
    Secondary and tertiary structure
  38. What are secondary structures?
    Refers to a local spatial arrangement of the polypeptide backbone
  39. What kind of bonds do secondary structures mostly rely on?
    Hydrogen bonds
  40. What are two common arrangements for secondary protein structures?
    • α-helix
    • β sheet
  41. How are α-helices formed/stabilized?
    By H bonds between nearby residues
  42. How are β sheets formed/stabilized?
    By H bonds between adjacent segments that may not be nearby
  43. Do secondary structures fulfill all hydrogen bonds internally or externally?
    Internally
  44. What is an irregular arrangement of a polypeptide chain called?
    Random coil
  45. How is the backbone of an α-helix held together?
    By H bonds between the backbone amides of an n and n+4 amino acids
  46. A right-handed helix has about how many residues per turn?
    3.6
  47. Describe the organization of α-helices
    • Peptide bonds are aligned roughly parallel with the helical axiz
    • Side chains point out and are roughly perpendicular with the helical axis
  48. How are peptide bonds aligned with respect to the helical axis?
    Parallel with the axis
  49. How are side chains organized on an α-helix?
    • Point out
    • Roughly perpendicular with the axis
  50. Which amino acids generally don't exist in an α-helix?
    • Proline
    • Glycine
  51. Why don't α-helices have the amino acid proline in their structure?
    • Proline tends to break them (not covalently though)
    • Can't make hydrogen bonds so the structure just gets weird
  52. Why don't α-helices have the amino acid glycine in their structure?
    Glycine is too flexible to be stable in α-helices
  53. What are the two ways α-helices can twist?
    • Right-handed
    • Left-handed
  54. Where's the dipole moment in a peptide bond?
    • Carbonyl O negative
    • Amide H positive
  55. Which bonds in an α-helix have similar orientation?
    Peptide bonds
  56. The α-helix has a large _________ dipole moment
    macroscopic
  57. Negatively charged residues often occur near which end of the helix dipole?
    Positive end
  58. What kind of residues often occur near the positive end of the helix dipole?
    Negatively charged residues
  59. What are supersecondary structures/motifs?
    Intermediate structures between secondary and tertiary structures
  60. How do supersecondary structures come about?
    Result from packing specific adjacent secondary structure motifs
  61. What are some examples of supersecondary structure motifs?
    • Coiled coils in keratin
    • Superhelix in collagen
  62. What are coiled coils in keratin?
    • α-helices wrapped around one another and then arranged parallel in length
    • Forms a protofilament
  63. What are superhelices in collagen?
    Chains twisted together forming a 3 stranded helix
  64. What is hair made of?
    Coiled α-helices
  65. Why aren't coiled coils considered tertiary structures?
    • They're well organized
    • Only consist of α-helices
  66. How are hair dressers doing biochemistry?
    • There are disulfide bonds in hair
    • Disulfide bonds join α-helices
    • Reduce with moist heat -> weakens H bonds
    • Curl and then oxidize to form bonds again
  67. How do β sheet structures arise?
    • Due to planarity of the peptide bond
    • Tetrahedral geometry of the α-carbon
  68. How is the β sheet structure held together?
    By hydrogen bonds between the backbone amides in different strands
  69. What is the orientation of side chains in β sheets?
    Protrude from the sheet in alternating up and down directions
  70. What are the two orientations that β sheets come in?
    • Parallel
    • Antiparallel
  71. What are the H bonds like in parallel β sheets?
    • H-bonded strands run in the same direction
    • Resulting in bent H bonds (weaker)
  72. What are the H bonds like in antiparallel β sheets?
    • H-bonded strands run in opposite directions
    • Resulting in linear H bonds (stronger)
  73. How are β strands usually depicted?
    As a "pointed blade"
  74. What are β turns?
    Whenever strands in β sheets change direction
  75. How often do β turns occur?
    Frequently
  76. How are 180° β turns accomplished?
    • Over 4 amino acids
    • Stabilized by a hydrogen bond from a carbonyl oxygen to amide proton three residues down the sequence
  77. How can secondary structures be assessed?
    By circular dichroism
  78. What is circular dichroism?
    • A molecule will absorb circularly polarized light differently depending on structure
    • Left-handed vs. right-handed
  79. What kind of graph is used to measure circular dichroism?
    Absorbance vs. wavelength (nm)
  80. What does the absorbance vs. wavelength plot for circular dichroism tell you?
    • Simply how many of the type of structure there are
    • Not exactly how they're structured
  81. What bonds are involved in tertiary and quaternary structures of proteins?
    • Ionic bonds
    • Hydrogen bonds
    • Disulfide bonds
    • Van der waal's forces
    • Hydrophobic interactions
  82. What was the first protein whose tertiary structure was determined?
    Myoglobin
  83. How was myoglobin's tertiary structure determined?
    From X-ray studies by Kendrew and Perutz
  84. What is a chaperone?
    A protein whose job it is to help other proteins fold correctly
  85. Why are chaperones necessary, even though Anfinsen Experiment showed that nothing else was needed for the protein to fold properly?
    As proteins get larger, they have harder time folding
  86. What cool quaternary structure of a protein provides a specialized environment for other proteins to fold?
    GroEL/GroES
  87. What is GroEL/GroES?
    • Quaternary structure w/ a specialized environment for other proteins to fold in
    • Double barrel structure
    • 7 identical subunits per barrel
    • 14 identical subunits total
  88. Where are all the subunits of GroEL/GroES made?
    • In the cytosol
    • And they somehow come together
  89. How do proteins fold so quickly and correctly?
    Definitely not trial and error cuz that would take too long, trying to sample every option
  90. What is protein denaturation?
    • Loss of 3D structure sufficient to cause a loss of function
    • No secondary structure either
  91. How can proteins be denatured?
    • Heat
    • Extreme pH
    • Organic solutes and solvents
    • Detergents
  92. Protein denaturation is cooperative...
    Yup
  93. What is proteostasis in cells?
    • Continual maintenance of the necessary set of active cellular proteins
    • Gotta keep the number of functional proteins the same
  94. Proteostasis requires regulation of what?
    • Synthesis
    • Folding
    • Refolding
    • Degradation
  95. What generally happens when systems regulating proteostasis malfunction?
    Usually leads to disease states
  96. What are some pathways contributing to proteostasis?
    • Polypeptide; folding intermediate; native protein; misfolded protein; aggregation; autophagy; peptide fragments
    • Polypeptide; folding intermediate; aggregation; autophagy; peptide fragments
    • Polypeptide; folding intermediate; remodeling; misfolded protein; aggregation; autophagy; peptide fragments
    • etc. etc.
  97. What are two main families of chaperones?
    • Hsp70
    • Chaperonins (10-15% of proteins)
  98. Where is Hsp70 more abundant?
    • In cells that are stressed by elevated temperatures
    • Heat shock protein
  99. What does Hsp70 do?
    Can help folding or prevent folding when needed
  100. What are some examples of chaperonins?
    • E.coli- GroEL/GroES
    • Eukaryotes- analog is called Hsp60
  101. What is amyloidoses?
    Diseases in which there is deposit of insoluble amyloid fibers due to misfolding of proteins
  102. What are some examples of amyloidoses?
    • Alzheimers
    • Parkinson's
    • Huntington's
  103. What are amyloid fibrils?
    • High amt in cells
    • Contribute to cell death
  104. What happens if proteostasis fails to destroy/autophage the aggregation of misfolded proteins?
    Diseases
  105. What are prions and why are they dangerous?
    • Normal proteins that exist in the brain tissue in all mammals in one very stable state that's not pathogenic
    • Under certain circumstances, can form another stable structure of β sheets
    • Because of β sheets, they aggregate
    • This causes functional problems (in brain) so neurons die
    • In the pathogenic form, prion proteins are hard to detect and extremely hard to denature or destroy
  106. What causes spongiform encephalopathies?
    • Pathogenic prions
    • PrPc → PrPsc
    • They interact, causes PrPsc folding

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Mursizzle
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MCB 102 Lec 4 Protein structure
Updated:
2016-07-11 00:02:23
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MCB 102 Lec Protein structure
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MCB 102 Lec 4 Protein structure
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