Week 4 HW: Protein Design Part I

Shuguang Zhang Questions Answers:

1. Why do humans eat beef but do not become cows, eat fish but do not become fish? The human body only digests the fish into its nutritional constituents, such as amino acids. Humans lack the biological capacity to reverse translate the amino acid sequence back into the mRNA sequence and reverse transcribe it back into DNA. Basically, humans aren’t able to do the Central Dogma in reverse. Humans also do not have the natural ability to incorporate dietary genes of the consumed animals into their genome.

2. Why are there only 20 natural amino acids? According to chemical biologist Andrew Doig of The University of Manchester, it largely comes down to the 20 AAs’ ability to do redox reactions and their hydrophobicity. The 1952 Miller-Urey experiment shows that with the conditions of earth billions of years ago, it was capable to make more than just the 20 proteinogenic AAs. The majority of the hydrophobic AAs are necessary for forming a stable and soluble protein structure with a close-packed cores without gaps. While the ability to do redox reactions is necessary for protecting the AAs from oxygen free-radicals that are more abundant at that current time.

3. Where did amino acids come from before enzymes that make them, and before life started? The 1952 Miller-Urey experiment attempted to simulate the conditions of a primordial Earth inside a flask. In the flask, they combined ammonia, hydrogen, methane, and water vapor plus electrical sparks, which resulted in the formation of amino acids. They hypothesized that the conditions in the flask mirrors early Earth’s conditions and created chemical reactions that forms the first organic compounds, dubbed the primordial soup. 4. If you make an α-helix using D-amino acids, what handedness (right or left) would you expect? Left. 5. Why do β-sheets tend to aggregate? β-sheets tend to aggregate because they are set up to form hydrogen bonds with other β-sheets, creating an insoluble structure. 6. Why do many amyloid diseases form β-sheets? β-sheets aggregation is thermodynamically stabler to form, leading to β-sheets aggregating with other β-sheets and self-assembly tendencies, forming amyloids. These amyloids are very stable and insoluble, and propagate through misfolding surrounding proteins.

References: Alraawi, Z., Banerjee, N., Mohanty, S., & Kumar, T. K. S. (2022). Amyloidogenesis: What Do We Know So Far? International Journal of Molecular Sciences, 23(22), 13970. https://doi.org/10.3390/ijms232213970

Brazil, R. (2018, September 17). Why are there 20 amino acids? Chemistry World. https://www.chemistryworld.com/features/why-are-there-20-amino-acids/3009378.article

Hoang, H. N., Abbenante, G., Hill, T. A., Ruiz-Gómez, G., & Fairlie, D. P. (2012). Folding pentapeptides into left and right handed alpha helices. Tetrahedron, 68(23), 4513–4516. https://doi.org/10.1016/j.tet.2011.10.108

Richardson JS, Richardson DC. Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2754-9. doi: 10.1073/pnas.052706099. PMID: 11880627; PMCID: PMC122420.