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971c: Ebola glycoprotein peptide inhibitor design
Status: Closed


Name: 971c: Ebola glycoprotein peptide inhibitor design
Status: Closed
Created: 08/20/2014
Points: 100
Expired: 08/27/2014 - 14:00
Difficulty: Intermediate
Description: We would like you to design a small (25-residue) peptide that can bind to and block the Ebola glycoprotein. The glycoprotein is a viral surface protein that allows the Ebola virus to enter human cells. A small peptide inhibitor of this protein would therefore represent a candidate therapeutic for treating this deadly disease. We are starting you with a hotspot "stub" that was the top-scoring result from the earlier stub-finding puzzle, number 846. (Congratulations to AnthropicDreams!) We have extended this stub with twenty-two additional residues that you can design. A small peptide in this size range probably won't fold the way a protein would. Some considerations -- good hydrophobic packing, lack of holes in the core, good hydrogen bonding, presence of secondary structure, etc. -- will be the same, but in addition, heavy disulfide cross-linking is often necessary for stability in this size range. You will get a considerable bonus for forming up to three disulfide bonds (for a total of five, counting the two disulfide bonds already present in the Ebola target protein). Many natural plant and animal toxins are small peptides, and it is common to see three disulfide bonds in a "leapfrog" pattern (i.e. cys1-cys4, cys2-cys5, cys3-cys6) for maximal stability. The starting point for this puzzle has three disulfides in this "leapfrog" pattern, but this might not be the optimal disulfide placement or backbone topology. Feel free to change the secondary structure, move the disulfides around, or otherwise improve on this!
Categories: Design, Overall

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wisky's picture
User offline. Last seen 22 weeks 2 days ago. Offline
Joined: 07/13/2011
Would like to see!

I would like to see this puzzle in different sizes, like 25, 35, and 45 residues with the 3 cystine bond pattern requirement! I think that would give you guys a nice big set of good designs to pick from.

Susume's picture
User offline. Last seen 6 hours 38 min ago. Offline
Joined: 10/02/2011
There's more info and

There's more info and diagrams for some "leapfrog" disulfide patterns here: http://www.cyclotide.com/knots.html

The page says cystine knots are 26-48 residues long, so 25 may be at the lower limit of what will fold up that way. I agree with wisky - I'd like to work on longer versions too.

v_mulligan's picture
User offline. Last seen 1 year 23 weeks ago. Offline
Joined: 03/04/2009
Groups: None

Thanks a lot for posting this, Susume!

wisky's picture
User offline. Last seen 22 weeks 2 days ago. Offline
Joined: 07/13/2011
Also would like to see

Also would like to be able to remove and insert residues from this protein

Joined: 10/30/2012
Groups: Beta Folders
me also, inserting gives some

me also, inserting gives some creative options, as it is this one is pretty close to what was given.

v_mulligan's picture
User offline. Last seen 1 year 23 weeks ago. Offline
Joined: 03/04/2009
Groups: None
Definitely a challenge

I know that 25 residues is definitely a challenge. We picked this size for two reasons: first, it's in a size range that is nicely compatible with chemical synthesis. Large proteins must be expressed in bacteria or yeast, but with a small enough peptide, we have the option of artificially synthesizing the peptide. This allows for inclusion of nonstandard amino acids and other unnatural modifications that can add new functionality, as well as for large-scale production of fairly pure peptide. Unfortunately, the longer the peptide, the harder it is to synthesize and get good yields and high purity. I wanted to keep the peptide short enough that synthesis is a very feasible option.

Second, where large proteins are difficult to get into the body and difficult to get across barriers, a sufficiently small peptide (particularly if compact and ordered) has the potential for oral bioavailability, which makes it easier to use as a drug.

In short, if we keep it small, we might have some of the advantages of both small-molecule drugs (which get into the body easily and are easy to produce in large amounts, but which are usually pretty nonspecific) and proteins (which can have terrific specificity and affinity for a target, meaning a potent desired effect with few side-effects, but which don't get into the body easily). That's the hope, anyways!

bkoep's picture
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Joined: 11/15/2012
Groups: None
Advanced deadline

We have advanced the deadline for this puzzle by several hours to accommodate a scheduled server outage: http://fold.it/portal/node/998369

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