Q1. You aim to chemically synthesize four peptides with the following one-letter amino acid sequences: TIGER, PANTHER, CHEETAH, and CAT. a) Which one of these peptides will have the lo
biochemistry project and need an explanation and answer to help me learn.
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1. Students may work alone or in groups consisting of up to 4 students, all of whom are associated with the same GSI (not necessarily the same Discussion section). Groups should submit a single copy of their work with the names of all participants on it. You are responsible for making sure that the assigned person in your group includes your name on the project submission, and submits the project within the deadline.
2. Projects should be submitted to the Canvas website of YOUR MCDB 310 discussion section and NOT to the general course Canvas site. This ensures that your project ends up with the correct GSI. The answers should NOT be submitted directly to Dr. Nandakumar or Dr. Akey (please see exception below for late submissions). The GSIs will grade them all and then post the scores in the Assignment folder.
3. Deadline for submission is Sunday, January 22nd 11:59 PM. Resubmissions, even if they are within the deadline, will not be accepted. We can consider submissions that are late but by no more than 24 hours past the deadline. However, these late submissions will be graded for no more than ? credit (i.e. a maximum score of 5/10). These late submissions will have to be emailed directly to Dr. Nandakumar, because Canvas will not accept late submissions. Submissions attempted after the 24-hour late period will NOT be accepted.
4. You cannot receive fractional credit. For e.g. for a 1 point question with two parts, you can only be awarded the point if you get both parts correct no 0.5 points awarded.
PROJECT 1 (Three questions with each containing several parts)
Q1. You aim to chemically synthesize four peptides with the following one-letter amino acid sequences: TIGER, PANTHER, CHEETAH, and CAT.
a) Which one of these peptides will have the lowest pI? Give a reason for your answer. You are not expected to calculate the pIs of the peptides to answer this question. A qualitative knowledge of the ionization properties of amino acids discussed in class is sufficient to answer this question. 2 points.
b) Based on what we learned in the lectures, draw the titration curve for the TIGER peptide in the pH range 0-14. Make sure to label the two axes, and put labels for the pK1, pK2, and pKR terms on the curve or on the y-axis. If there are multiple R groups that titrate, indicate the pKRs as pKR-E, pKR-R etc so that it is clear which R group you are talking about. You are not required to write out the chemical structures of the various titration intermediates. 2 points.
c) While entering the sequence in into the automated peptide synthesizer you mistakenly type in CHETAH instead of CHEETAH. So, you synthesize a peptide with the wrong sequence. However, you realize something is wrong as soon as you do a pH titration of the peptide. What is one difference between the pH titration curves for the peptides CHEETAH and CHETAH? You can either answer in words alone or with help of pH titration curves. 1 point.
Q2. Since learning about non-covalent interactions, proteins, and protein structure, you decide to re-visit an informational video that talks about the structure of the SARS CoV-2 virus on YouTube:
Note: although you are encouraged to watch the full video, the questions below can be answered by watching only the first 8 ? minutes.
The video mentions the spike protein that forms the basis for the name corona of coronaviruses, and is the protein that binds receptor proteins on the human cell surface to give rise to infection. In Chapter 4, we have learned about techniques for determining the 3D structure of proteins. The video talks about a cutting-edge technique for solving the 3D structure of the entire spike protein. What is this technology called? 1 point.
In Chapter 3, we learned that proteins often contain modified amino acids. What is the modification that is abundant in the spike protein and what is the amino acid (out of the 20 we learned in class) that is modified? 1 point.
We learned about two major secondary structural elements found in proteins (Chapter 4). What secondary structure within the spike protein is primarily involved in binding to the human host receptor protein? 1 point.
What is the quaternary structure of the spike protein (Chapter 4)? Be as specific as you can (e.g., homodimer, heterohexamer, etc?? and not just dimer, hexamer, etc??). 1 point.
A structure of a part of the spike protein (receptor binding domain) bound to the human cell surface ACE2 receptor was solved by X-ray crystallography, a technique that was mentioned in Chapter 4. Of the four types of non-covalent interactions we learned about in Chapter 2, which one is predominantly responsible for the interaction of the spike protein with the ACE2 receptor? 1 point.
Q3. The whole world has been reeling for the last year or two from the onslaught of the Omicron variant and its subvariants (latest one is called XBB.1.5). The original vaccines developed again COVID-19 use the spike protein of the original Wuhan strain as an antigen to generate antibodies in our body that would specifically bind the spike protein (using the same four interactions we learned in Chapter 2). By helping us develop antibodies that can bind the spike protein, the vaccines help us to neutralize the virus if/when we are exposed to it after we have developed immunity from vaccination. Any mutation in the spike protein that increases its binding affinity (i.e., strength of the interaction) for the ACE2 receptor will likely make the virus more transmissible! Similarly, any mutation in the spike protein that disrupts interactions with the antibodies we have from immunization can potentially reduce the efficacy of the vaccine in preventing breakthrough infection! Based on what you have learned thus far in the biochemistry course, you decide to do some more research to get some insights into these important questions regarding the Omicron variant Why is it more transmissible? Why does it cause more breakthrough cases?
You first want to learn more about the original strain (called wild type in biology). The first thing you do is go to protein sequence database and enter COVID-19 spike protein in the search bar. The first hit (P0DTC2 ? SPIKE_SARS2) is the spike protein of the original strain. You click on the link to open the page with a lot of information about this protein. You want to first look at its sequence, so you click the Sequence tab on the left. Make sure you can follow the numbering scheme of the amino acids of the protein. You will need this skill to answer some questions below. Make sure you are able to appreciate that the polypeptide is 1273 amino acids long.
Click on Copy sequence link above the sequence of the protein to answer the following questions:
To answer the sub-parts of this question, first go to and paste the sequence (starting from MFV??.. and ending with ????HYT) of the spike protein. Click compute parameters. Use the information that comes from this to answer the questions.
Is the spike protein an acidic or basic protein? Give a reason for your answer. 1 point.
What is the molecular weight of the protein based on this analysis? You run a size-exclusion column of the native spike protein and it suggests that the molecular weight of the native spike protein is ~423 kDa (or ~423,000 Da). Give a reason for why the two molecular weight numbers dont match up. 2 points.
The Omicron variant is much more transmissible than the original strain and scientists reason that some of the 30+ mutations in its spike protein allow it to bind the human ACE2 receptor with greater binding affinity than the spike protein of the original strain, making it more transmissible. You want to figure out if indeed the mutations in Omicron spike protein help it bind the ACE2 receptor with stronger affinity. Below is a list of some of the mutations in the Omicron variant spike protein and the corresponding amino acid in the human ACE2 receptor that the indicated spike protein amino acids interact with (using some of the 4 interactions we learned in Chapter 2). E.g., amino acid # 498 of the original strain and # 498 (which is an R) in the Omicron strain spike protein interact with amino acid D38 of the human ACE2 receptor using one of the four interaction we learned in chapter 2.
What is the amino acid in the original strain (denoted by ?) at each of the listed amino acid # in the table that got mutated in the Omicron strain? Look at the sequence of the original strain spike protein in Uniprot to figure this out. 2 points.
Now that you know what amino acid of the original strain is mutated to what amino acid in the Omicron variant, you want to figure out will the mutation change the binding affinity of the spike protein to the receptor. For each of these mutations, mention whether you think they make the binding of Omicron spike protein to the ACE2 receptor stronger, weaker, or leave it unaffected. Give a reason for your answer in each of the four cases. 4 points.
Based on the information provided in this Project and the knowledge gained from solving the questions above, give a plausible reason for why the Omicron variant and its subvariants like XBB.1.5 are resulting in reinfections as well as infections (although mostly mild) in fully vaccinated individuals? 1 point.
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