viosca Lv 1
For those of us with older hardware, it would be very helpful if the delete and insert tools were available on these huge puzzles. This would let us build up a design in stages.
976: Abeta binder full-length design
Closed since over 11 years ago
Intermediate Overall DesignSummary
- Created
- August 30, 2014
- Expires
- Max points
- 100
Due to CASP, it has been a while since we've posted an Alzheimer's disease puzzle. In this puzzle, we would like you to design a binder for the ABeta42 polypeptide that can bind to and stabilize the polypeptide in an alpha-helical conformation. You will get a bonus for forming up to three disulfide bonds.
The ABeta peptide is a fragment of a larger human protein called APP. APP is a membrane protein found on the surface of cells in the brain and other tissues. It has a hydrophobic segment that is inserted into the cell membrane, forming an alpha-helix. When APP is cleaved by proteases, a fragment consisting of part of the transmembrane domain and part of the extracellular domain results: the ABeta peptide. This peptide is quite hydrophobic and aggregation-prone. It also has considerable propensity to adopt beta-sheet rich structures, ultimately forming beta-rich amyloid aggregates. Either these aggregates, or some of the intermediates along the aggregation pathway, are neurotoxic and cause the massive neuronal death seen in Alzheimer's disease.
It is our hope that a protein that is able to bind to Abeta when it is in a soluble state (before it enters the aggregation cascade) could help to prevent aggregation, and ultimately be used as an Alzheimer's therapy. Keeping Abeta in its alpha-helical conformation should help to prevent it from converting to the beta-rich conformation that permits amyloid formation. In this puzzle, the starting structure has the transmembrane portion of the Abeta peptide in a helical conformation, and this is what we would like you to build a protein around. You can move this from the starting conformation, but try not to get too far from an alpha-helical conformation. Good luck, and as always, be sure to share your most interesting designs with the scientists, independent of your score!
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