Week 4 HW: Protein Design Part 1

Part A : Conseptual Questions

Questions from Shuguang Zhang: (i.e. you can select two to skip)

  1. How many molecules of amino acids do you take with a piece of 500 grams of meat? (on average an amino acid is ~100 Daltons)

  2. Why do humans eat beef but do not become a cow, eat fish but do not become fish? Because DNA determines what organism you are, not the food you eat. When we eat meat, proteins are broken down into amino acids and then cells use those amino acids to build human proteins, based on the instructions in our human DNA.

  3. Why are there only 20 natural amino acids? Evolution “settled” on 20 because:

  • They provide enough chemical diversity (acidic, basic, hydrophobic, etc.) to build all the proteins needed for life.
  • Adding more would require more complex machinery (tRNA, enzymes) without big advantages.
  • Some organisms have a 21st (selenocysteine) or 22nd (pyrrolysine), but 20 is the standard set used by almost all life.

  1. Can you make other non-natural amino acids? Design some new amino acids.

  2. Where did amino acids come from before enzymes that make them, and before life started? Amino acids formed abiotically (without life) on early Earth. Miller–Urey experiment (1953) showed that sparking a mixture of simple gases (methane, ammonia, hydrogen, water vapor) produces amino acids. So they likely formed in:

  • Volcanic vents
  • Lightning strikes in early atmosphere
  • Outer space (found in meteorites)

  1. If you make an α-helix using D-amino acids, what handedness (right or left) would you expect? Left-handed. Natural proteins use L-amino acids, which form right-handed α-helices. D-amino acids are mirror images, so they form left-handed α-helices.

  2. Can you discover additional helices in proteins? Yes! Besides the α-helix, there are:

  • 3₁₀-helix (tighter, 3 amino acids per turn)
  • π-helix (wider, 4.4 amino acids per turn)
  • Polyproline helix (type I and II, no H-bonds inside helix)

Scientists still find new variations, especially in designed peptides.

  1. Why are most molecular helices right-handed? Most molecular helices, such as alpha-helices in proteins and B-DNA, are right-handed because this conformation is more energetically stable and structurally favorable. This preference arises because L-amino acids (in proteins) and D-sugars (in DNA) fit together more efficiently in a right-handed twist, minimizing steric hindrance and maximizing stabilizing hydrogen bonds. Another answer :
  • In a left-handed helix with L-amino acids, side chains bump into the backbone.
  • So evolution selected for right-handed α-helices in proteins.
  • DNA helices are right-handed (B-DNA) due to sugar-phosphate backbone geometry and base stacking.
  1. Why do β-sheets tend to aggregate? What is the driving force for β-sheet aggregation? Driving forces:
  • Hydrogen bonding between backbone N-H and C=O groups of different strands.
  • Hydrophobic interactions between side chains.
  • Van der Waals packing.

β-strands have “sticky” edges that can pair with other strands, leading to aggregation, especially if the protein misfolds.

  1. Why do many amyloid diseases form β-sheets? Can you use amyloid β-sheets as materials? In diseases like Alzheimer’s, proteins misfold into cross-β structure—long, stacked β-sheets that are very stable and insoluble, forming plaques. Yes! Amyloid fibers are super strong. Researchers use them for:
  • Nanowires (coated with metal)
  • Hydrogels for tissue engineering
  • Biosensors
  • Drug delivery
  1. Design a β-sheet motif that forms a well-ordered structure.

Part B: Protein Analysis and Visualization