Question

You have two enzymes Ayain (left) and Colease (right) and experimental evidence that the green and blue amino acids shown above form an active site in each case. You wish to use Al to study the likely structure of the active site in detail. This will give you information to help select possible drugs that fit the active site and will be tested in future experiments. You know the amino acid sequence of each protein and produce Alphafold predictions with the Predicted Aligned Error shown above. You only have enough funding and time to study one of the predictions in more detail. Which do you choose and why? (10)

Answer 1

To make a decision on which enzyme to study in detail—Ayain or Colease—based on the available information, we should consider a few key aspects:

1. Predicted Aligned Error (PAE): The PAE scores provide insight into the confidence of the predicted structural model. A lower PAE indicates higher reliability in the prediction of the active site structure and surrounding regions.

   • Check which enzyme has a lower PAE score around the active site region. More reliable predictions allow for better interpretations and potential drug interactions.

2. Active Site Characteristics: Analyze the specific characteristics of the active sites between Ayain and Colease. The functional relevance and the uniqueness of the active sites could influence our choice.

   • For example, if one enzyme's active site is more unique or has a crucial role in a disease mechanism, it may warrant further investigation despite slightly higher PAE.

3. Biological Relevance: Consider the biological context of both enzymes—if one enzyme is associated with more critical pathways, diseases, or targets (e.g., antibiotic resistance, cancer, etc.), it could prioritize that enzyme for detailed study.

4. Potential for Drug Development: Think about the likelihood of finding effective drug candidates based on structural predictions. If one enzyme’s active site is more amenable to drug binding based on known structures or previous studies, it may be more beneficial to select that enzyme.

5. Resources for Assays: If there are existing assays or systems established for one enzyme but not the other, that could influence the decision.

Based on these points, you would select the enzyme with the following criteria:

• If Ayain has consistently lower PAE scores, indicating a more reliable structure prediction around its active site, this would make it a better candidate for in-depth analysis. A lower PAE means you can be more confident in any structural insights generated, which could greatly facilitate drug design.

Conversely, if Colease demonstrates significant unique active site features that are critically relevant to a disease state, even with slightly higher PAE values, that might sway the decision.

Ultimately, the decision should be based on a combination of the PAE, biological context, drug design potential, and existing assay frameworks.