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marsfan's picture
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Why do the COVID-19 binder design puzzles have us designing a binding protein entirely from scratch? We know what protein binds there in nature. Why not start with that as a base for the docking side, and then modify the other parts of the protein to change what it does once it is bound? Would it not be faster that way to find a good design if we already have a functional design for the docking?

If it is because we do not know how the naturally occurring proteins fold, why not use their design as a starting point, and then try to refine the folding with electron density puzzles?

HMK's picture
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Good idea! ACE2

That's a good idea! Maybe I will get some inspiration for the next Corona-binder-puzzle from pdb.
For example: https://www.rcsb.org/3d-view/ngl/6lzg
or
https://www.rcsb.org/structure/6M0J

bkoep's picture
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Yes!

That's a great point! We do know exactly how the natural ACE2 receptor binds to the CoV spike, so we can use the known binding interface to assist our design.

In fact, that is the premise of our Beginner Coronavirus puzzle, and that was also the strategy behind the Round 3 and Round 4 puzzles in the Coronavirus Binder series.

There are a few reasons we haven't focused exclusively on that strategy:
1. The existing Foldit tools are not very good for this approach. Tools like Remix and the Blueprint Panel don't work very well in the regions around a frozen backbone (like frozen helix from ACE2). We can fix some of these issues in the future, and we're working on it.

2. The ACE2 protein is not optimized to bind the spike target. ACE2 is a human protein that normally helps to regulate cardiovascular behavior; it has been "hijacked" by CoV for infection, but ACE2 is not evolved to bind the CoV spike target. Clearly it is capable of binding the CoV spike, but we think that we can develop better binding modes.

3. That approach doesn't play to Foldit's strengths. Since we already know the ACE2 binding helix, we have automated protein design tools that can easily stitch that helix into different scaffolds, and indeed other researchers are already working on that. However, it's much harder for our automated tools to invent new binding modes from scratch. We think this is an area where Foldit players can excel, so we are trying to focus our efforts on discovering new binding modes.

marsfan's picture
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bkoep, that makes sense now

bkoep, that makes sense now that I think about it. We are playing to Foldit's strengths by starting from scratch.

Also, I was not even thinking about the fact that ACE2 is not technically supposed to bind to the spike, but that it just happens to do so.

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