BDD coursework Questions (2025-26) – Approved Final Version
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According to the previous literature cited by the authors, a subpopulation of soluble misfolded proteins successfully bypasses the refolding action of chaperones like GroEL, Dak, and HtpG. Describe the core molecular mechanism by explaining
a) The key structural characteristic of the bypassing of the misfolded states relative to the native state. [10 Marks]
b) How this structural characteristic fundamentally interferes with the chaperone’s ability to identify and bind the misfolded state for refolding.
[10 Marks]
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The authors concluded that the research data suggested that the misfolded soluble protein states are kinetically long-lived because they involve non-native changes in non- covalent so called “lasso” entanglements.
a) According to the evidence provided by the authors, what are the two required structural components that define a non-covalent lasso entanglement in a protein? [10 Marks]
b) Explain why a non-native change in this entanglement (e.g., a non-native gain of entanglement) makes it an energetically costly and slow process to reach the proteins final native state? [10 Marks]
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The overall meta-analysis of experimental time courses led the authors to conclude that the soluble misfolded protein states typically take “days or longer” to fold.
a) The authors arrived at this conclusion by applying a double exponential fit to the refolding data. What specific kinetic time scale derived from this fit is interpreted as the folding time of the soluble misfolded protein fraction? [10 Marks]
b) The average duration of the experimental time courses used was approximately 150 minutes , what does the discrepancy between the experimental duration and the calculated folding time imply about the folding status of the misfolded subpopulation at the experiment’s final time point? [10 Marks]
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As described in the paper in vitro refolding experiments involving ATP-dependent chaperones, such as GroEL/GroES, produce some misfolded soluble proteins, one possible explanation for the persistent misfolded fraction is that the chaperones became inactive due to ATP depletion. To disprove this, the authors used a kinetic model of ATP-dependent folding. Explain the main pieces of evidence the authors presented to conclude that ATP depletion does not contribute to the Lack of refolding.
[20 Marks}
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The authors began their investigation by referencing in vivo studies, such as the effect of synonymous mRNA variants on proteins like Chloramphenicol
acetyltransferase (CATIII) and FREQUENCY (FRQ)
a) Explain the significance of observing decreased protein activity/function (i.e., misfolding) after introducing a synonymous mutation. [10 Marks]
b) How does this in vivo evidence serve as the necessary foundation for the authors’ subsequent in vitro meta-analysis; in terms of the problem the researchers are trying to solve? [10 Marks]
End of Assessment
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